Phthalazinones and isoquinolinones as rock inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

CROSS REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 14/759,495, filed onJul. 7, 2015 (now allowed) which is a 371 of International ApplicationNo. PCT/US2014/011957, filed on Jan. 17, 2014, which claims the benefitof U.S. Provisional Application Ser. No. 61/754,007 filed on Jan. 18,2013 which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to novel phthalazinone andisoquinolinone compounds, and their analogues thereof, which areinhibitors of Rho kinases, compositions containing them, and methods ofusing them, for example, for the treatment or prophylaxis of disordersassociated with aberrant Rho kinase activity.

BACKGROUND OF THE INVENTION

Rho-Kinase (ROCK) is a member of the serine-threonine protein kinasefamily. ROCK exists in two isoforms, ROCK1 and ROCK2 (Ishizaki, T. etal., EMBO J., 15:1885-1893 (1996)). ROCK has been identified as aneffector molecule of RhoA, a small GTP-binding protein (G protein) thatplays a key role in multiple cellular signaling pathways. ROCK and RhoAare ubiquitously expressed across tissues. The RhoA/ROCK signalingpathway is involved in a number of cellular functions, such as ACTIN®organization, cell adhesion, cell migration, and cytokinesis (Riento, K.et al., Nat. Rev. Mol. Cell Biol., 4:446-456 (2003)). It is alsodirectly involved in regulating smooth muscle contraction (Somlyo, A.P., Nature, 389:908-911 (1997)). Upon activation of its receptor, RhoAis activated, and, in turn, it activates ROCK. Activated ROCKphosphorylates the myosin-binding subunit of myosin light chainphosphatase, which inhibits activity of the phosphatase and leads tocontraction. Contraction of the smooth muscle in the vasculatureincreases blood pressure, leading to hypertension.

There is considerable evidence in the literature that the Rho A/ROCKsignaling pathway plays an important role in signal transductioninitiated by several vasoactive factors, for example angiotensin II(Yamakawa, T. et al., Hypertension, 35:313-318 (2000)), urotension II(Sauzeau, V. et al., Circ. Res., 88:1102-1104 (2001)), endothelin-1(Tangkijvanich, P. et al., Hepatology, 33:74-80 (2001)), serotonin(Shimokawa, H., Jpn. Circ. J., 64:1-12 (2000)), norepinephrine(Martinez, M. C. et al., Am. J. Physiol., 279:H1228-H1238 (2000)) andplatelet-derived growth factor (PDGF) (Kishi, H. et al., J. Biochem.,128:719-722 (2000)). Many of these factors are implicated in thepathogenesis of cardiovascular disease.

Additional studies in the literature, some using the known ROCKinhibitors fasudil (Asano, T. et al., J. Pharmacol. Exp. Ther.,241:1033-1040 (1987)) or Y-27632 (Uehata, M. et al., Nature, 389:990-994(1997)) further illustrate the link between ROCK and cardiovasculardisease. For example, ROCK expression and activity have been shown to beelevated in spontaneously hypertensive rats, suggesting a link to thedevelopment of hypertension in these animals (Mukai, Y. et al., FASEBJ., 15:1062-1064 (2001)). The ROCK inhibitor Y-27632 (Uehata, M. et al.,Nature, ibid.) was shown to significantly decrease blood pressure inthree rat models of hypertension, including the spontaneouslyhypertensive rat, renal hypertensive rat and deoxycortisone acetate salthypertensive rat models, while having only a minor effect on bloodpressure in control rats. This reinforces the link between ROCK andhypertension.

Other studies suggest a link between ROCK and atherosclerosis. Forexample, gene transfer of a dominant negative form of ROCK suppressedneointimal formation following balloon injury in porcine femoralarteries (Eto, Y. et al., Am. J. Physiol. Heart Circ. Physiol.,278:H1744-H1750 (2000)). In a similar model, ROCK inhibitor Y-27632 alsoinhibited neointimal formation in rats (Sawada, N. et al., Circulation,101:2030-2033 (2000)). In a porcine model of IL-1 beta-induced coronarystenosis, long term treatment with the ROCK inhibitor fasudil was shownto progressively reduce coronary stenosis, as well as promote aregression of coronary constrictive remodeling (Shimokawa, H. et al.,Cardiovascular Res., 51:169-177 (2001)).

Additional investigations suggest that a ROCK inhibitor would be usefulin treating other cardiovascular diseases. For example, in a rat strokemodel, fasudil was shown to reduce both the infarct size and neurologicdeficit (Toshima, Y., Stroke, 31:2245-2250 (2000)). The ROCK inhibitorY-27632 was shown to improve ventricular hypertrophy, fibrosis andfunction in a model of congestive heart failure in Dahl salt-sensitiverats (Kobayashi, N. et al., Cardiovascular Res., 55:757-767 (2002)).

Other animal or clinical studies have implicated ROCK in additionaldiseases including coronary vasospasm (Shimokawa, H. et al., Cardiovasc.Res., 43:1029-1039 (1999)), cerebral vasospasm (Sato, M. et al., Circ.Res., 87:195-200 (2000)), ischemia/reperfusion injury (Yada, T. et al.,J. Am. Coll. Cardiol., 45:599-607 (2005)), pulmonary hypertension(Fukumoto, Y. et al., Heart, 91:391-392 (2005)), angina (Shimokawa, H.et al., J. Cardiovasc. Pharmacol., 39:319-327 (2002)), renal disease(Satoh, S. et al., Eur. J. Pharmacol., 455:169-174 (2002)) and erectiledysfunction (Gonzalez-Cadavid, N. F. et al., Endocrine, 23:167-176(2004)).

In another study, it has been demonstrated that inhibition of theRhoA/ROCK signaling pathway allows formation of multiple competinglamellipodia that disrupt the productive migration of monocytes(Worthylake, R. A. et al., J. Biol. Chem., 278:13578-13584 (2003)). Ithas also been reported that small molecule inhibitors of Rho Kinase arecapable of inhibiting MCP-1 mediated chemotaxis in vitro (Iijima, H.,Bioorg. Med. Chem., 15:1022-1033 (2007)). Due to the dependence ofimmune cell migration upon the RhoA/ROCK signaling pathway one wouldanticipate inhibition of Rho Kinase should also provide benefit fordiseases such as rheumatoid arthritis, psoriasis, and inflammatory boweldisease.

The above studies provide evidence for a link between ROCK andcardiovascular diseases including hypertension, atherosclerosis,restenosis, stroke, heart failure, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension andangina, as well as renal disease and erectile dysfunction. Given thedemonstrated effect of ROCK on smooth muscle, ROCK inhibitors may alsobe useful in other diseases involving smooth muscle hyper-reactivity,including asthma and glaucoma (Shimokawa, H. et al., Arterioscler.Thromb. Vase. Biol., 25:1767-1775 (2005)). Furthermore, Rho-kinase hasbeen indicated as a drug target for the treatment of various otherdiseases, including airway inflammation and hyperresponsiveness (Henry,P. J. et al., Pulm. Pharmacol Ther., 18:67-74 (2005)), cancer (Rattan,R. et al., J Neurosci. Res., 83:243-255 (2006); Lepley, D. et al.,Cancer Res., 65:3788-3795 (2005)), fibrotic diseases (Jiang, C. et al.,nt. J Mol. Sci., 13:8293-8307 (2012); Zhou, L. et al., Am. J. Nephrol.,34:468-475 (2011)), as well as neurological disorders, such asspinal-cord injury, Alzheimer's disease, multiple sclerosis, stroke andneuropathic pain (Mueller, B. K. et al., Nat. Rev. Drug Disc., 4:387-398(2005); Sun, X. et al., J. Neuroimmunol., 180:126-134 (2006)).

There remains an unmet medical need for new drugs to treatcardiovascular disease. In the 2012 update of Heart Disease and StrokeStatistics from the American Heart Association (Circulation, 125:e2-e220(2012)), it was reported that cardiovascular disease accounted for 32.8%of all deaths in the U.S., with coronary heart disease accounting for ˜1in 6 deaths overall in the U.S. Contributing to these numbers, it wasfound that ˜33.5% of the adult U.S. population was hypertensive, and itwas estimated that in 2010˜6.6 million U.S. adults would have heartfailure. Therefore, despite the number of medications available to treatcardiovascular diseases (CVD), including diuretics, beta blockers,angiotensin converting enzyme inhibitors, angiotensin blockers andcalcium channel blockers, CVD remains poorly controlled or resistant tocurrent medication for many patients.

Although there are many reports of ROCK inhibitors under investigation(see, for example, US 2012/0122842 A1, US 2010/0041645 A1, US2008/0161297 A1, and Hu, E. et al., Exp. Opin. Ther. Targets, 9:715-736(2005)), fasudil is the only marketed ROCK inhibitor at this time. Ani.v. formulation was approved in Japan for treatment of cerebralvasospasm. There remains a need for new therapeutics, including ROCKinhibitors, for the treatment of cardiovascular diseases, cancer,neurological diseases, renal diseases, fibrotic diseases, bronchialasthma, erectile dysfunction, and glaucoma.

SUMMARY OF THE INVENTION

The present invention provides novel phthalazinone and isoquinolinonecompounds, their analogues, including stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof, which are usefulas selective inhibitors of Rho kinases.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of conditions associated with aberrant ROCK activity.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a conditionassociated with aberrant ROCK activity.

In another aspect, the present invention is directed to a method oftreating a cardiovascular or related disease which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above. Examples of such diseases that maybe treated include, for example, hypertension, atherosclerosis,restenosis, stroke, heart failure, renal failure, coronary arterydisease, peripheral artery disease, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, pulmonary hypertension, angina,erectile dysfunction and renal disease.

In another aspect, the present invention is directed to a method oftreating diseases involving smooth muscle hyper reactivity includingasthma, erectile dysfunction and glaucoma, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In another aspect, the present invention is directed to a method oftreating diseases mediated at least partially by Rho kinase includingfibrotic diseases, oncology, spinal-cord injury, Alzheimer's disease,multiple sclerosis, stroke, neuropathic pain, rheumatoid arthritis,psoriasis and inflammatory bowel disease, which method comprisesadministering to a patient in need of such treatment a compound of thepresent invention as described above.

In yet additional aspects, the present invention is directed atpharmaceutical compositions comprising the above-mentioned compounds,processes for preparing the above-mentioned compounds and intermediatesused in these processes.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—;

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 15-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, carbocycle and heterocycle are substitutedwith 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—C(O)O-alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—O(CH₂)_(n)carbocycle, —O(CH₂)_(n)heterocycle, —O(CH₂)_(n)NR^(a)R^(a),—(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle, wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂,CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

provided

1) when L is NHC(O), R¹ is other than

wherein X is N or a substituted or unsubstituted carbon atom;

2) when L is NR⁶, R¹ is heterocycle substituted with 1-4 R⁷.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is CR¹⁰;

L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 15-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy;

R⁴ is H;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and 4-10 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p),wherein said alkyl, carbocycle and heterocycle are substituted with 1-4R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₁₋₄ alkoxy, —NR⁸R⁸, —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁹, at each occurrence, is independently selected from halogen, OH, C₁₋₄alkyl, C₁₋₄ alkoxy;

R¹⁰ is selected from H and C₁₋₄ alkyl;

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle,SO₂alkyl, SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(II) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10 membered heterocycle selected from

wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R⁷; and

other variables are as defined in Formula (II) above.

In another aspect, the present invention provides compounds of Formula(II) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); and

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

other variables are as defined in Formula (II) above.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—;

R¹ is heteroaryl substituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

other variables are as defined in Formula (I) above.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—;

R¹ is selected from

other variables are as defined in Formula (I) above.

In still another aspect, the present invention provides compounds ofFormula (IV):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle, and 5- to 10-memberedheterocycle, wherein said carbocycle and heterocycle are substitutedwith 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (I) above.

In still another aspect, the present invention provides compounds ofFormula (IV), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); and

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

other variables are as defined in Formula (IV) above.

In still another aspect, the present invention provides compounds ofFormula (IV), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); and

other variables are as defined in Formula (IV) above.

In another aspect, the present invention provides compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

M is selected from N and CR¹⁰;

L is selected from C₁₋₂ alkylene substituted with 1-2 R⁴, wherein one orboth carbon atoms and the groups attached thereto are replaced by O,NR⁶, and C(O);

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 15-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, carbocycle and heterocycle are substitutedwith 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—C(O)O-alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO(C₁₋₄ alkyl), CO₂H,CO₂(C₁₋₄ alkyl), —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—O(CH₂)_(n)carbocycle, —O(CH₂)_(n)heterocycle, —O(CH₂)_(n)NR^(a)R^(a),—(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle, wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R^(b);

R¹⁰ is selected from H and C₁₋₄ alkyl;

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂,CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

provided

(1) when L is NHC(O), R¹ is other than

wherein X is N or a substituted or unsubstituted carbon atom;

(2) when L is NH, R¹ is other than

(3) when L is O, R¹ is other than

In another aspect, the present invention provides compounds of Formula(V):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is selected from —CR⁴R⁴C(O)—, —OC(O)—, —NR⁶C(O)—, and —NR⁶—;

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 15-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

R², at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R³, at each occurrence, is independently selected from halogen, C₁₋₆alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, —CH₂OH, —OCH₂F,—OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H,—CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —C(═NH)NH₂, carbocycle, andheterocycle, wherein said alkyl, alkoxy, alkylthio, haloalkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁴, at each occurrence, is independently selected from H, OH, NH₂,CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl), —N(C₁₋₄alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H, CH₂CO₂(C₁₋₄alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, wherein said alkyl,alkoxy, haloalkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and —(CR⁶R⁶)_(n)-4-10 membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, carbocycle and heterocycle are substitutedwith 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 15-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—C(O)O-alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)carbocycle, —O(CH₂)_(n)heterocycle,—O(CH₂)_(n)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, OH,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂,CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

provided

(1) when L is NHC(O), R¹ is other than

wherein X is N or a substituted or unsubstituted carbon atom;

(2) when L is NR⁶, R¹ is heteroaryl substituted with 1-4 R⁷.

In another aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR^(B), O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle,SO₂alkyl, SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d);

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VI) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ is selected from H, C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle,—(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10 membered heterocycle selected from

wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R⁷; and

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(VI) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); and

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

other variables are as defined in Formula (VI) above.

In another aspect, the present invention provides compounds of Formula(VII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;and

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(V) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—;

R⁷, at each occurrence, is independently selected from H, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

other variables are as defined in Formula (V) above.

In another aspect, the present invention provides compounds of Formula(V) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

L is —NR⁶—; and

R¹ is selected from

other variables are as defined in Formula (V) above.

In still another aspect, the present invention provides compounds ofFormula (VIII):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle, and 5- to 10-memberedheterocycle, wherein said carbocycle and heterocycle are substitutedwith 1-4 R⁷;

R⁵, at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10 memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p), wherein said alkyl, carbocycle, and heterocycleare substituted with 1-4 R⁷;

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 1-4 R⁷;

R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹;

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is independently selected from 0, 1, and 2;

other variables are as defined in Formula (V) above.

In still another aspect, the present invention provides compounds ofFormula (VIII), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein

R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHC₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O H, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, —NHCO-carbocycle,—NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p), wherein said alkyl, alkenyl, alkynyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹;

alternatively, R⁸ and R⁸ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b);

R^(a), at each occurrence, is independently selected from H, C₁₋₄ alkyl,—(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b);

R^(b), at each occurrence, is independently selected from ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl),CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c);

R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); and

R^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p);

other variables are as defined in Formula (VIII) above.

In still another aspect, the present invention provides compounds ofFormula (VIII), or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, wherein:

R¹ is NR⁵R⁵;

R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹;

R⁸, at each occurrence, is independently selected from H, C₁₋₄ alkyl,C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-cycloalkyl, —(CH₂)_(n)-phenyl, and—(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, and heterocycleare substituted with 0-4 R⁹; and

R⁹, at each occurrence, is independently selected from halogen, OH, NO₂,CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(C R¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); and

other variables are as defined in Formula (VIII) above.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), and (IV), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein M is N or CR¹⁰; L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and—NR⁶C(O—; R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to12-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycleand heterocycle are substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 12-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—, and —NR⁶—; R¹ is 4- to 12-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p) and substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)— or NR⁶—; R¹ is selected from

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is —NR⁶C(O)—; R¹ is C₃₋₁₀ carbocycle substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—; R¹ is C₃₋₆ cycloalkyl substitutedwith 1-4 R⁷ or aryl substituted with 1-4 R⁷; R⁷, at each occurrence, isindependently selected from H, ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN,OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸,—NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄alkyl), —NHCO₂(CH₂)₃O (C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂,—NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl),—NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (IV), (V), and (VIII), or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein L is selected from —NR⁶C(O)—; R¹ is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or phenyl, each substituted with 1-4 R⁷; R⁷, ateach occurrence, is independently selected from H, ═O, halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H, —(CH₂)_(n)—CO₂(C₁₋₄alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O (C₁₋₄ alkyl),—NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄ alkyl)₂,—NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵, at each occurrence, is independently selected from H,C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and —(CR⁶R⁶)_(n)-4-10membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said carbocycle andheterocycle are substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵, at each occurrence, is independently selected from H,C₁₋₄ alkyl, —(CH₂)_(n)—C₃₋₁₀ carbocycle, —(CH₂)_(n)-aryl,—(CH₂)_(n)-4-10 membered heterocycle selected from

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form 4- to 10-membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p),wherein said heterocycle is substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is NR⁵R⁵; R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂,—NHC(O)NH(C₁₋₄ alkyl), —NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is selected from

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4- to 12-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,NR⁸, O, and S(O)_(p); wherein said alkyl, carbocycle and heterocycle aresubstituted with 1-4 R⁷; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷.

In one embodiment, the present invention provides compounds of Formulae(I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof, wherein L is selected from —CR⁴R⁴C(O)—, —OC(O)—, and —NR⁶C(O)—;R¹ is selected from C₃₋₁₀ carbocycle and 4- to 12-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, NR⁸, O, andS(O)_(p); wherein said carbocycle and heterocycle are substituted with1-4 R⁷; R⁵, at each occurrence, is independently selected from H, C₁₋₄alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle substituted with 1-4 R⁷, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle selected from

alternatively, R⁵ and R⁵ are taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values ≤10 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values ≤1 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values ≤0.1 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values ≤0.05 μM.

In another embodiment, the compounds of the present invention have ROCKIC₅₀ values ≤0.01 μM.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s).

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a condition associated with aberrantROCK activity comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof. Asused herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” covers the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a patient that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state. In another embodiment, the present inventionprovides a combined preparation of a compound of the present inventionand additional therapeutic agent(s) for simultaneous, separate orsequential use in therapy.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

II. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms.

Alkyl group can be unsubstituted or substituted with at least onehydrogen being replaced by another chemical group. Example alkyl groupsinclude, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), andpentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Similarly, “alkylthio” or “thioalkoxy”represents an alkyl group as defined above with the indicated number ofcarbon atoms attached through a sulphur bridge; for example methyl-S—and ethyl-S—.

“Halo” or “halogen” includes fluoro (F), chloro (Cl), bromo (Br), andiodo (I). “Haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogens.Examples of haloalkyl include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl,pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, andheptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” thatis intended to include both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁ to C₆ haloalkoxy” or “C₁₋₆ haloalkoxy”,is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups.Examples of haloalkoxy include, but are not limited to,trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy.Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example trifluoromethyl-S—, andpentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbomyl. Branchedcycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropylare included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclichydrocarbon ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes.

Parenteral administration may be used where the ester per se is active,or in those instances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “saturated” for saturated, “MW” for molecularweight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or“Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “6” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

-   Me Methyl-   Et Ethyl-   Pr Propyl-   i-Pr Isopropyl-   Bu Butyl-   i-Bu Isobutyl-   t-Bu tert-butyl-   Ph Phenyl-   Bn Benzyl-   Boc tert-butyloxycarbonyl-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN Azobisisobutyronitrile-   BBr₃ boron tribromide-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   CBz Carbobenzyloxy-   CH₂Cl₂ Dichloromethane-   CH₃CN or ACN Acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ Chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DCM dichloromethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or diisopropylethylamine Hunig's base-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5 S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimthylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH Ethanol-   GMF glass microfiber filter-   Grubbs (II)    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    (phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid-   Hex Hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂SO₄ sulfuric acid-   K₂CO₃ potassium carbonate-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH Methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ Ammonia-   NH₄C₁ ammonium chloride-   NH₄OH ammonium hydroxide-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS polystyrene-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis.

IV. Biology In Vitro Assays

The effectiveness of compounds of the present invention as ROCKinhibitors can be determined in a 30 μL assay containing 20 mM HEPES, pH7.5, 20 mM MgCl₂, 0.015% Brij-35, 4 mM DTT, 5 μM ATP and 1.5 μM peptidesubstrate (FITC-AHA-AKRRRLSSLRA-OH). Compounds were dissolved in DMSO sothat the final concentration of DMSO was <2%, and the reaction wasinitiated with Rho kinase variants. After incubation, the reaction wasterminated by the addition of EDTA and the phosphorylated andnon-phosphorylated peptides separated using a LABCHIP® 3000 Reader(Caliper Life Sciences). Controls consisted of assays that did notcontain compound, and backgrounds consisted of assays that containedenzyme and substrate but had EDTA from the beginning of the reaction toinhibit kinase activity. Compounds were tested in dose-response format,and the inhibition of kinase activity was calculated at eachconcentration of compound. The inhibition data were fit using acurve-fitting program to determine the IC₅₀; i.e., the concentration ofcompound required to inhibit 50% of kinase activity.

Representative Examples were tested in the ROCK assay described aboveand found having ROCK inhibitory activity. A range of ROCK inhibitoryactivity (IC₅₀ values) of ≤50 μM (50000 nM) was observed. Table A belowlists the ROCK IC₅₀ values measured for the following examples. IC₅₀ranges against ROCKs are as follows: +++=0.1-100 nM; ++=101-1000 nM;+=1001-50000 nM.

TABLE A Example No. ROCK1 IC₅₀ (nM) ROCK2 IC₅₀ (nM) 1 − +++ 2 ++ +++ 3++ +++ 4 − ++ 5 − ++ 6 − ++ 7 − +++ 8 − + 9 + +++ 10 ++ +++ 11 + ++12 + + 13 + + 14 + + 15 + + 16 + + 17 + +++ 18 + + 19 + + 20 + ++ 21 +++++ 22 + + 23 ++ +++ 24 ++ +++ 25 ++ +++ 26 + +++ 27 + +++ 28 + ++ 29 ++++ 30 − − 31 + +++ 32 − − 33 +++ +++ 34 + ++ 35 ++ +++ 36 + +++ 37 +++++ 38 ++ +++ 39 ++ +++ 40 ++ +++ 41 +++ +++ 42 + +++ 43 + ++ 44 + +++45 − +++ 46 + +++ 47 ++ +++ 48 ++ +++ 49 − +++ 50 +++ +++ 51 + +++ 52 ++++ 53 +++ +++ 54 ++ +++ 55 + + 56 + + 57 + + 58 +++ +++ 59 + + 60 ++++++ 61 +++ +++ 62 +++ +++ 63 ++ +++ 64 ++ +++ 65 +++ +++ 66 +++ +++ 67++ +++ 68 − +++ 69 + ++ 70 + +++ 71 + +++ 72 ++ +++ 73 ++ +++ 73 − −74 + +++ 75 +++ +++ 76 +++ +++ 77 +++ +++ 78 ++ +++ 79 +++ +++ 80 ++++++ 81 + ++ 82 + ++ 83 +++ +++ 84 ++ +++ 85 +++ +++ 86 ++ +++ 87 ++ +++88 + +++ 89 ++ +++ 90 ++ +++ 91 + +++ 92 ++ +++ 93 +++ +++ 94 +++ +++ 95+++ +++ 96 ++ +++ 97 ++ ++ 98 +++ +++ 99 +++ +++ 100 +++ +++ 101 +++ +++102 +++ +++ 103 +++ +++ 104 +++ +++ 105 ++ +++ 106 + +++ 107 +++ +++ 108++ +++ 109 +++ +++ 110 +++ +++ 111 ++ ++ 112 + ++ 113 ++ ++ 114 ++ +++115 +++ +++ 116 +++ +++ 117 +++ +++ 118 ++ +++ 119 ++ +++ 120 +++ +++121 ++ +++ 122 +++ +++ 123 ++ +++ 124 ++ +++ 125 +++ +++ 126 ++ +++ 127+++ +++ 128 +++ +++ 129 +++ +++ 130 +++ +++ 131 +++ +++ 132 +++ +++ 133++ +++ 134 ++ +++ 135 ++ +++ 136 + +++ 137 +++ +++ 138 +++ +++ 139 ++++++ 140 +++ +++ 141 +++ +++ 142 +++ +++ 143 + + 144 +++ +++ 145 +++ +++146 +++ +++ 147 +++ +++ 148 +++ +++ 149 +++ +++ 150 +++ +++ 151 +++ +++152 +++ +++ 153 +++ +++ 154 +++ +++ 155 +++ +++ 156 +++ +++ 157 +++ +++158 +++ +++ 159 +++ +++ 160 +++ +++ 161 +++ +++ 162 +++ +++ 163 +++ +++164 +++ +++ 165 +++ +++ 166 ++ +++ 167 +++ +++ 168 +++ +++ 169 +++ +++170 +++ +++ 171 +++ +++ 172 +++ +++ 173 +++ +++ 174 +++ +++ 175 +++ +++176 +++ +++ 177 +++ +++ 178 ++ +++ 179 +++ +++ 180 +++ +++ 181 ++ +++182 +++ +++ 183 +++ +++ 184 +++ +++ 185 +++ +++ 186 ++ +++ 187 +++ +++188 +++ +++ 189 +++ +++ 190 +++ +++ 191 +++ +++ 192 ++ +++ 193 + ++ 194++ +++ 195 +++ +++ 196 + ++ 197 +++ +++ 198 +++ +++ 199 +++ +++ 200 ++++++ 201 +++ +++ 202 +++ +++ 203 ++ +++ 204 ++ +++ 205 ++ +++ 206 +++ +++207 +++ +++ 208 +++ +++ 209 ++ ++ 210 ++ ++ 211 + ++ 212 ++ +++ 213 ++++++ 214 +++ +++ 215 ++ ++ 216 + ++ 217 + ++ 218 + ++ 219 +++ +++ 220 ++++++ 221 ++ ++ 222 +++ +++ 223 +++ +++ 224 +++ +++ 225 +++ +++ 226 ++++++ 227 ++ +++ 228 +++ +++ 229 +++ +++ 230 +++ +++ 231 ++ +++ 232 ++ +++233 ++ ++ 234 ++ +++ 235 +++ +++ 236 ++ +++ 237 ++ +++ 238 ++ +++ 239 +++++ 240 ++ +++ 241 +++ +++ 242 ++ +++ 243 − − 244 +++ +++ 245 +++ +++246 +++ +++ 247 +++ +++ 248 ++ +++ 249 +++ +++ 250 ++ +++ 251 ++ +++252 + ++ 253 + ++ 254 ++ +++ 255 + ++ 256 ++ +++ 257 + +++ 258 +++ +++259 ++ +++ 260 ++ +++ 261 +++ +++ 262 ++ +++ 263 ++ +++ 264 +++ +++ 265+++ +++ 266 +++ +++ 267 ++ +++ 268 +++ +++ 269 + +++ 270 +++ +++ 271 ++++++ 272 +++ +++ 273 ++ +++ 274 +++ +++ 275 +++ +++ 276 + +++ 277 ++ +++278 ++ +++ 279 ++ +++ 280 ++ +++ 281 ++ +++ 282 ++ +++ 283 +++ +++ 284+++ +++ 285 +++ +++ 286 ++ +++ 287 +++ +++ 288 +++ +++ 289 +++ +++ 290+++ +++ 291 ++ +++ 292 ++ +++ 293 ++ +++ 294 ++ +++ 295 ++ +++ 296 +++++ 297 +++ +++ 298 +++ +++ 299 ++ +++ 300 +++ +++ 301 +++ +++ 302 ++++++ 303 ++ +++ 304 ++ +++ 305 + + 306 ++ +++ 307 ++ +++ 308 +++ +++ 309+++ +++ 310 ++ +++ 311 +++ +++ 312 ++ +++ 313 +++ +++ 314 +++ +++ 315+++ +++ 316 ++ +++ 317 +++ +++ 318 +++ +++ 319 +++ +++ 320 +++ +++ 321+++ ++ 322 +++ ++ 323 +++ +++ 324 +++ +++ 325 ++ +++ 326 +++ ++ 327 ++++++ 328 ++ +++ 329 +++ +++ 330 +++ ++ 331 ++ +++ 332 +++ +++ 333 +++ +++334 +++ +++ 335 +++ +++ 336 +++ +++ 337 +++ +++ 338 +++ ++ 339 +++ +++340 +++ +++ 341 +++ +++ 342 +++ +++ 343 +++ +++ 344 +++ +++ 345 ++ +++346 + ++ 347 + ++ 348 ++ +++ 349 +++ +++ 350 +++ +++ 351 +++ +++ 352 +++ 353 ++ +++ 354 +++ +++ 355 + +++ 356 +++ ++ 357 + ++ 358 ++ +++ 359 ++++ 360 + +++ 361 ++ +++ 362 + +++ 363 + +++ 364 ++ +++ 365 + 221.80 366++ +++ 367 + +++ 368 + +++ 369 ++ +++ 370 + +++ 371 ++ ++ 372 ++ ++ 373+++ +++ 374 +++ +++ 375 +++ +++ 376 ++ +++ 377 + +++ 378 +++ +++ 379 +++++ 380 ++ +++ 381 +++ +++ 382 +++ +++ 383 ++ +++ 384 ++ +++ 385 +++ +++386 ++ +++ 387 + +++ 388 ++ +++ 389 ++ +++ 390 ++ +++ 391 ++ +++ 392 ++++++ 393 +++ +++ 394 ++ +++ 395 +++ +++ 396 ++ +++ 397 + ++ 398 ++ +++399 ++ ++ 400 +++ +++ 401 +++ +++ 402 ++ +++ 403 +++ +++ 404 +++ +++ 405+++ +++ 406 +++ +++ 407 +++ +++ 408 ++ +++ 409 − − 410 − − 411 − − 412 −−

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the patient to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of ROCK. Such compounds may beprovided in a commercial kit, for example, for use in pharmaceuticalresearch involving ROCK. For example, a compound of the presentinvention could be used as a reference in an assay to compare its knownactivity to a compound with an unknown activity. This would ensure theexperimentor that the assay was being performed properly and provide abasis for comparison, especially if the test compound was a derivativeof the reference compound. When developing new assays or protocols,compounds according to the present invention could be used to test theireffectiveness.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a cardiovascular and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat cardiovascular and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by methodsavailable to those skilled in the art of organic chemistry (Maffrand, J.P. et al., Heterocycles, 16(1):35-37 (1981)). General synthetic schemesfor preparing compounds of the present invention are described below.These schemes are illustrative and are not meant to limit the possibletechniques one skilled in the art may use to prepare the compoundsdisclosed herein. Different methods to prepare the compounds of thepresent invention will be evident to those skilled in the art.Additionally, the various steps in the synthesis may be performed in analternate sequence in order to give the desired compound or compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al., (Protective Groups in Organic Synthesis,4th Edition, Wiley-Interscience (2006)).

Scheme 1 shows the synthesis of generic compounds 1e, 1f, 1g, from thecommon intermediate 1d. Suzuki-Miyaura coupling between aryl halide 1aand boronic acid or boronate ester (1b) in the presence of a base suchas K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords intermediate 1c.Cleavage of the protecting group, such as using TFA or HCl in dioxanewhen PG=Boc, affords the arylamine intermediate 1d. Intermediate 1d isconverted to the urea target 1e by treatment with an isocyanate or acarbamic chloride. Intermediate 1d is converted to the amide target 1fby treatment with an acid chloride in the presence of a base such aspyridine or DIEA. Alternatively, Target 1f is prepared by coupling ofintermediate 1d with a carboxylic acid in the presence of a couplingreagent, such as HATU or BOP, and a base such as DIEA. Intermediate 1dis converted to the carbamate target 1g by treatment with achloroformate in the presence of a base such as DIEA or TEA.

Alternatively, targets 1e-g can be prepared as shown in Scheme 2. Arylhalide 2a (commercially available or prepared by literature methods) isconverted to the aryl boronic acid or boronate ester 2b by coupling withbis(pinacolato)diboron in the presence of a base such a potassiumacetate and a catalyst such as PdCl₂(dppf) in dioxane or DMSO.Suzuki-Miyaura coupling between aryl halide 1a and boronic acid orboronate ester (2b) in the presence of a base such as K₃PO₄ and acatalyst such as Pd(PPh₃)₄ affords target compounds 1e-g.

Alternatively, target 1e can be prepared as shown in Scheme 3 beginningfrom isocyanate 3a, which is either commercially available or can beprepared from the aniline precursor upon treatment with phosgene (orequivalent) and an appropriate base such as TEA. Intermediate 3a isreacted with amine (3b) to afford urea 3c. Suzuki-Miyaura couplingbetween aryl halide 1a and boronic acid or boronate ester (3c) in thepresence of a base such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄affords target compounds 1e.

Scheme 4 shows the synthesis of carbamate target 4e, beginning fromchloroformate 4a (either commercially available or prepared by treatmentof an appropriate halophenol with phosgene or a phosgene equivalent).Intermediate 4a is reacted with an amine (4b) in the presence of a basesuch as TEA to afford carbamate 4c. Aryl halide 4c is converted to thearyl boronic acid or boronate ester 4d by coupling withbis(pinacolato)diboron in the presence of a base such a potassiumacetate and a catalyst such as PdCl₂(dppf) in dioxane or DMSO.Suzuki-Miyaura coupling between aryl halide 1a and boronic acid orboronate ester (4d) in the presence of a base such as K₃PO₄ and acatalyst such as Pd(PPh₃)₄ affords target compound 4e.

Scheme 5 shows the synthesis of amide target 5e, beginning with boronicacid/ester 5a, which is either commercially available or is preparedfrom the aryl halide precursor. Suzuki-Miyaura coupling between arylhalide 1a and boronic acid or boronate ester (5a) in the presence of abase such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords intermediate5b. Cleavage of the protecting group (PG) by alkaline hydrolysis (orother reagents as appropriate) affords carboxylic acid 5c. Coupling ofintermediate 5c with amine 5d in the presence of a coupling reagent,such as HATU or BOP, and a base such as DIEA affords target 5e.

Scheme 6 shows an alternate synthesis to target 5e beginning from acid6a. Coupling of intermediate 6a with amine 6b in the presence of acoupling reagent, such as HATU or BOP, and a base such as DIEA affordsintermediate amide 6c. Aryl halide 6c is converted to the aryl boronicacid or boronate ester 6d by coupling with bis(pinacolato)diboron in thepresence of a base such a potassium acetate and a catalyst such asPdCl₂(dppf) in dioxane or DMSO. Suzuki-Miyaura coupling between arylhalide 1a and boronic acid or boronate ester (6d) in the presence of abase such as K₃PO₄ and a catalyst such as Pd(PPh₃)₄ affords targetcompound 5e.

Scheme 7 shows the synthesis of target 7b beginning with intermediateaniline 1d. Aniline 1d is coupled with heteroaryl halide 7a underthermal S_(N)Ar conditions in the presence of a base such as DIEA in asolvent such as DMF to afford 7b. Alternatively, 1d and 7a may becoupled under Buchwald-Hartwig N-arylation conditions using a base suchas Cs₂CO₃, a catalyst such as Pd₂(dba)₃ and an appropriate ligand toafford 7b.

Scheme 8 shows an alternative synthesis of target 7b, beginning fromintermediate 8a, which is either commercially available or can beprepared by literature methods. An appropriate protecting group isintroduced by treatment with a base such as potassium carbonate and aprotecting group reagent such as para-methoxybenzyl chloride to afford8b. Treatment of aryl bromide 8b with sodium azide, Cu₂O and a ligandsuch as proline affords aniline 8c. Aniline 8c is coupled withheteroaryl halide 7a under thermal S_(N)Ar conditions in the presence ofa base such as DIEA in a solvent such as DMF to afford intermediate 8d.Alternatively, 8c and 7a may be coupled under Buchwald-HartwigN-arylation conditions using a base such as Cs₂CO₃, a catalyst such asPd₂(dba)₃ and an appropriate ligand to afford intermediate 8d. Cleavageof the protecting group under appropriate conditions (TFA in the case ofa para-methoxybenzyl protecting group) affords target 7b.

Scheme 9 shows an alternative synthesis of target 7b, starting from arylbromide 8b. Coupling of intermediate 8b with heteroaryl amine 9a underBuchwald-Hartwig N-arylation conditions using a base such as Cs₂CO₃, acatalyst such as Pd₂(dba)₃ and an appropriate ligand affordsintermediate 8d. Cleavage of the protecting group under appropriateconditions (TFA in the case of a para-methoxybenzyl protecting group)affords target 7b.

Scheme 10 shows the synthesis of intermediate 1a, where X═N.Furan-2,5-dione 10a can be converted to intermediate 10b by treatmentwith a reagent such as hydrazine. Intermediate 10b is chlorinated bytreatment with a reagent such as POCl₃ to afford dichloro intermediate10c. Partial hydrolysis of 10c with a reagent such as AcOH affordsintermediate 1a.

Scheme 11 shows the synthesis of intermediate 1a, where X═CR.Intermediate 11a is brominated with a reagent such as NBS to affordintermediate 1a.

Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out using prepacked SiO₂ cartridges elutingwith either gradients of hexanes and EtOAc or DCM and MeOH unlessotherwise indicated. Reverse phase preparative HPLC was carried outusing C18 columns eluting with gradients of Solvent A (90% H₂O, 10%MeOH, 0.1% TFA) and Solvent B (10% H₂O, 90% MeOH, 0.1% TFA, UV 220 nm)or with gradients of Solvent A (90% H₂O, 10% ACN, 0.1% TFA) and SolventB (10% H₂O, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A(98% H₂O, 2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% H₂O, 0.05% TFA,UV 220 nm) (or) SunFire Prep C18 OBD 5μ 30×100 mm, 25 min gradient from0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1 (or) WatersXBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridgeC18, 19×10 mm, 5-μm particles; Solvent A: water with 20-mM ammoniumacetate; Solvent B: 95:5 acetonitrile:water with 20-mM ammonium acetate;Gradient: 25-65% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min.

Unless otherwise stated, analysis of final products was carried out byreverse phase analytical HPLC.

Method A:

SunFire C18 column (3.5 m C18, 3.0×150 mm). Gradient elution (1.0mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent B for 5min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) andSolvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method B:

XBridge Phenyl column (3.5 m C18, 3.0×150 mm). Gradient elution (1.0mL/min) from 10-100% Solvent B over 10 min and then 100% Solvent B for 5min was used. Solvent A is (95% water, 5% acetonitrile, 0.05% TFA) andSolvent B is (5% water, 95% acetonitrile, 0.05% TFA, UV 254 nm).

Method C:

Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 40° C.;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 1 mL/min.

Method D:

Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95methanol:water with 10 mM ammonium acetate; Mobile Phase B: 95:5methanol:water with 10 mM ammonium acetate; Temperature: 40° C.;Gradient: 0.5 min hold at 0% B, 0-100% B over 4 minutes, then a0.5-minute hold at 100% B; Flow: 0.5 mL/min.

Method E:

Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes; Flow: 1.11 mL/min.

Method F:

Waters BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes; Flow: 1.11 mL/min.

Intermediate 1: 2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)aceticacid

Intermediate 1A: Ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

To a vial containing a degassed (3× vacuum/Ar) mixture of ethyl2-(4-bromophenyl)acetate (1 g, 4.11 mmol), bis(pinacolato)diboron (1.25g, 4.94 mmol), and potassium acetate (1.21 g, 12.3 mmol) in dioxane (10mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (0.090 g, 0.123 mmol). Thereaction mixture was degassed, sealed and heated at 110° C. for 16 h.The mixture was diluted with water, then extracted with EtOAc. Theorganic phase was concentrated and purified via flash chromatography(EtOAc/hexane) to afford 1.1 g (92%) of Intermediate 1A. MS(ESI) m/z:291.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.84-7.71 (m, 2H), 7.34-7.28 (m,J=8.0 Hz, 2H), 4.15 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.27 (s, 12H),1.26-1.22 (m, 3H).

Intermediate 1B: Ethyl2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetate

To 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol), Intermediate 1A(386 mg, 1.33 mmol) and K₃PO₄ (588 mg, 2.77 mmol), were added dioxane (9mL) and water (1 mL). The mixture was degassed (evacuated and flushedwith Ar (5×)). Pd(PPh₃)₄ (64.0 mg, 0.055 mmol) was added, then themixture was degassed (2×). The reaction vial was sealed and heated in amicrowave reactor at 150° C. for 30 min. The reaction mixture wasconcentrated and purified via flash chromatography (EtOAc/hexane) toafford 218 mg (46%) of Intermediate 1B. MS(ESI) m/z: 309.1 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 8.46-8.28 (m, 1H), 7.99-7.82 (m,2H), 7.69 (d, J=7.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.45 (d, J=6.6 Hz, 2H),4.12 (qd, J=7.1, 1.8 Hz, 2H), 3.79 (s, 2H), 1.22 (td, J=7.0, 1.9 Hz,3H).

Intermediate 1

To a solution of Intermediate 1B (210 mg, 0.681 mmol) in MeOH (5 mL) andTHF (5 mL), was added 1M aq. lithium hydroxide (3.41 mL, 3.41 mmol). Themixture was stirred rt overnight, then was concentrated. The residue wasacidified with TFA, then was dissolved in DMSO/MeOH, and purifiedpreparative HPLC to afford 170 mg (89%) of Intermediate 1. MS(ESI) m/z:281.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.42-8.21 (m,1H), 7.99-7.82 (m, 2H), 7.77-7.62 (m, 1H), 7.59-7.50 (m, 2H), 7.49-7.37(m, J=8.3 Hz, 2H), 3.69 (s, 2H).

Intermediate 2: 5-((4-Methylpiperazin-1-yl)methyl)isoindoline, 3 TFA

Intermediate 2A: tert-Butyl di(prop-2-yn-1-yl)carbamate

To a solution of 2-propyn-1-amine and N-2-propynyl- (1.110 mL, 10.74mmol) in THF (20 mL) at rt, was added BOC₂O (2.58 g, 11.81 mmol). Tothis mixture was added TEA (0.150 mL, 1.074 mmol). The mixture wasstirred at rt for 14 h. The reaction mixture was concentrated to an oil.The oil was partitioned between 0.2 N HCl and EtOAc. The organic phasewas washed with H₂O, sat. NaHCO₃ and brine, dried (Na₂SO₄), filteredthrough a 1″ pad of SiO₂ and concentrated to afford 2.40 g (100%) ofIntermediate 2A as a yellow oil. MS(ESI) m/z: 216.1 (M+H)⁺; ¹H NMR (400MHz, CDCl₃) δ 4.17 (br. s., 4H), 2.22 (t, J=2.4 Hz, 2H), 1.48 (s, 9H).

Intermediate 2B: tert-Butyl 5-(hydroxymethyl)isoindoline-2-carboxylate

To a degassed (evacuated and flushed with Ar (5×)) solution ofprop-2-yn-1-ol (0.961 mL, 16.11 mmol) in toluene (5 mL) at 50° C., wereadded in 5 portions at 10 minute intervals Intermediate 2A (1.20 g, 5.37mmol) in degassed toluene (5 mL) and Tris(triphenylphosphine)rhodium(I)chloride (0.124 g, 0.134 mmol). Following the last addition, the brownmixture was stirred at 50° C. for 1.25 h. The reaction mixture wasconcentrated, then was co-evaporated with CHCl₃ (2×). The crude productwas purified by flash chromatography (0 to 100% ethyl acetate/hexanes,eluted at 75% EtOAc) to afford 1.15 g (86% yield) of Intermediate 2B asa white solid. MS(ESI) m/z: 521.3 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ7.33-7.21 (m, 3H), 4.63 (dd, J=5.6, 3.2 Hz, 4H), 4.60 (s, 2H), 1.52 (s,9H).

Intermediate 2C: tert-Butyl5-(((methylsulfonyl)oxy)methyl)isoindoline-2-carboxylate

To a solution of Intermediate 2B (500 mg, 2.006 mmol) in DCM (10 mL) at0° C., were added DIEA (0.420 mL, 2.407 mmol) and Ms-Cl (0.172 mL, 2.206mmol). The mixture was stirred at 0° C. for 1.5 h. The mixture wasdiluted with DCM, then was washed with half sat. NH₄C₁ and brine. Theorganic phase was dried (Na₂SO₄) and concentrated to afford 655 mg(100%) of Intermediate 2C as a brown oil. The material was used in thefollowing step without further purification. MS(ESI) m/z: 272.0(M-t-Bu+2H)⁺.

Intermediate 2D: tert-Butyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

To a solution of Intermediate 2C (657 mg, 2.007 mmol) in acetone (10 mL)at rt, were added K₂CO₃ (416 mg, 3.01 mmol) and 1-methyl piperazine(0.556 mL, 5.02 mmol). The mixture was stirred at rt for 2.5 h, then 1 hat 50° C. The mixture was concentrated, then was partitioned betweenEtOAc and H₂O. The aqueous phase was extracted with EtOAc (2×). Thecombined organic phase was dried (Na₂SO₄) and concentrated to affordIntermediate 2D as a brown oil. MS(ESI) m/z: 332.2 (M+H)⁺; ¹H NMR (400MHz, CD₃OD) δ 7.30-7.21 (m, 3H), 4.63 (dd, J=5.5, 2.0 Hz, 4H), 3.53 (s,2H), 2.50 (br. s., 8H), 2.27 (s, 3H), 1.52 (s, 9H).

Intermediate 2

Intermediate 2D was treated with 4N HCl in dioxane (5 mL, 20.00 mmol)and the resultant suspension was stirred for 1 h, then was concentrated.The mixture was redissolved in TFA (10 mL) and was stirred at rt for 20min. The mixture was concentrated. The brown oil was coevaporated withDCM (2×), ether, MeOH and CH₃CN to afford 1.36 g (100% yield, ˜85%purity) of Intermediate 2 as a brown semisolid, which was used as iswithout further purification. MS(ESI) m/z: 232.2 (M+H)⁺; ¹H NMR (400MHz, CD₃OD) δ 7.49-7.40 (m, 3H), 4.62 (s, 4H), 3.82 (s, 2H), 3.34 (br.s., 4H), 2.89 (s, 3H), 2.90 (br. s, 4H).

Intermediate 3: 4-(4-Aminophenyl)phthalazin-1(2H)-one, TFA salt

Intermediate 3A: tert-Butyl(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To 4-chlorophthalazin-1(2H)-one (118 mg, 0.653 mmol),(4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (170 mg, 0.719 mmol)and potassium phosphate (347 mg, 1.634 mmol), were added dioxane (9 mL)and water (1 mL). The mixture was degassed (evacuated and flushed withAr (5×)). Pd(PPh₃)₄ (37.8 mg, 0.033 mmol) was added, then the mixturewas degassed (2×). The reaction vial was sealed and heated in amicrowave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated and purified via flash chromatography to afford 150 mg(68%) of Intermediate 3A. MS(ESI) m/z: 338.1 (M+H)⁺.

Intermediate 3

To Intermediate 3A (150 mg, 0.445 mmol) in CH₂Cl₂ (3 mL), was added TFA(2 mL). The mixture was stirred rt for 2 h, then was concentrated. Thecrude product was purified via flash chromatography, then preparativeHPLC to afford 62 mg (59%) of Intermediate 3. MS(ESI) m/z: 238.1 (M+H)⁺;¹H NMR (500 MHz, CD₃OD) δ 8.44 (dt, J=4.7, 2.3 Hz, 1H), 7.97-7.87 (m,2H), 7.81-7.75 (m, 1H), 7.71-7.61 (m, 2H), 7.41-7.30 (m, 2H).

Intermediate 4:2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

Intermediate 4A: 2-(4-Bromo-2-fluorophenyl)-1-(isoindolin-2-yl)ethanone

To 2-(4-bromo-2-fluorophenyl)acetic acid (300 mg, 1.287 mmol),isoindoline (0.161 mL, 1.416 mmol), and HATU (587 mg, 1.545 mmol) in DMF(5 mL), was added DIEA (0.450 mL, 2.57 mmol). The mixture was stirred atrt for 1 h. The resultant heterogeneous mixture was diluted with EtOAc,then was washed with H₂O, 1 N HCl, H₂O, sat. NaHCO₃ and brine. Theorganic phase was dried (Na₂SO₄), filtered and concentrated. The crudeproduct was purified by flash chromatography (gradient from 0 to 100%ethyl acetate/hexanes) to afford 147 mg (34%) of Intermediate 4A as awhite solid. MS(ESI) m/z: 333.9 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ7.34-7.30 (m, 3H), 7.30-7.22 (m, 4H), 4.89 (s, 2H), 4.83 (s, 2H), 3.73(s, 2H)

Intermediate 4

To a mixture of Intermediate 4A (146 mg, 0.437 mmol),bis(pinacolato)diboron (133 mg, 0.524 mmol), and potassium acetate (129mg, 1.31 mmol) in a reaction vial, was added dioxane (3 mL). The mixturewas degassed (evacuated and flushed with Ar (3×)). PdCl₂(dppf) CH₂Cl₂adduct (9.6 mg, 0.013 mmol) was added, then reaction mixture wasdegassed (3× vacuum/Ar). The vial was sealed, then was heated at 110° C.for 2 h. The reaction mixture was diluted with EtOAc, then was washedwith H₂O and brine. The organic phase was dried (Na₂SO₄) andconcentrated. The crude product was purified by flash chromatography(gradient from 0 to 50% ethyl acetate/hexanes) to afford 120 mg (72%) ofIntermediate 4 as a yellow solid. MS(ESI) m/z: 386.1 (M+H)⁺; ¹H NMR (400MHz, CDCl₃) δ 7.55 (dd, J=7.5, 0.9 Hz, 1H), 7.50 (d, J=10.1 Hz, 1H),7.39 (t, J=7.4 Hz, 1H), 7.32-7.22 (m, 4H), 4.84 (s, 4H), 3.80 (s, 2H),1.33 (s, 12H).

Intermediate 5:2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

Intermediate 5A: 2-(4-Bromo-3-fluorophenyl)-1-(isoindolin-2-yl)ethanone

To a mixture of 2-(4-bromo-3-fluorophenyl)acetic acid (300 mg, 1.287mmol), isoindoline (0.161 mL, 1.416 mmol), and HATU (734 mg, 1.931 mmol)in DMF (5 mL), was add DIEA (0.450 mL, 2.6 mmol). The mixture wasstirred rt for 18 h. The reaction mixture was diluted with EtOAc, thenwas washed with H₂O, 1 N HCl, H₂O, sat. Na₂CO₃ and brine. The organicphase was dried (Na₂SO₄), filtered through a 1″ pad of SiO₂ andconcentrated. The crude product was purified by flash chromatography(gradient from 0 to 100% ethyl acetate/hexanes) to afford 379 mg (88%)of Intermediate 5A as an off-white solid. MS(ESI) m/z: 333.9 (M+H)⁺; ¹HNMR (400 MHz, CDCl₃) δ 7.50 (dd, J=8.0, 7.4 Hz, 1H), 7.33-7.22 (m, 4H),7.14 (dd, J=9.2, 2.0 Hz, 1H), 7.01 (dd, J=8.5, 1.9 Hz, 1H), 4.83 (s,4H), 3.72 (s, 2H).

Intermediate 5

To a mixture of Intermediate 5A (200 mg, 0.598 mmol),bis(pinacolato)diboron (182 mg, 0.718 mmol), and potassium acetate (176mg, 1.80 mmol) in a reaction vial, was added dioxane (5 mL). The mixturewas degassed (evacuated and flushed with Ar (3×)). PdCl₂(dppf) CH₂Cl₂adduct (13 mg, 0.018 mmol) was added, then the reaction mixture wasdegassed (3× vacuum/Ar). The vial was sealed, then was heated at 110° C.for 2 h. Additional catalyst (13 mg) was added and the reaction mixturewas stirred at 110° C. for 2 more hours. The reaction mixture was cooledto room temperature, then was filtered and concentrated. The crudeproduct was purified by flash chromatography (gradient from 0 to 100%ethyl acetate/hexanes) to afford 208 mg (91%) of Intermediate 5 as ayellow solid. MS(ESI) m/z: 386.1 (M+H)⁺; ¹H NMR (400 MHz, CDCl₃) δ 7.71(t, J=6.9 Hz, 1H), 7.35-7.20 (m, 4H), 7.13 (d, J=7.5 Hz, 1H), 7.04 (d,J=10.1 Hz, 1H), 4.83 (s, 2H), 4.77 (s, 2H), 3.78 (s, 2H), 1.35 (s, 12H).

Intermediate 6: 4-Bromoisoquinolin-1(2H)-one

To a solution of isoquinolin-1(2H)-one (105 mg, 0.723 mmol) in DMF (2mL), was added NBS (142 mg, 0.796 mmol). The mixture was stirred at rtfor 2 h, then was concentrated. The crude product was purified viapreparative HPLC to afford 110 mg (68%) of Intermediate 6. MS(ESI) m/z:223.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.57 (br. s., 1H), 8.24 (dd,J=8.0, 0.8 Hz, 1H), 7.88-7.83 (m, 1H), 7.79-7.75 (m, 1H), 7.61 (ddd,J=8.0, 7.1, 1.1 Hz, 1H), 7.55 (s, 1H).

Intermediate 7: 2-(4-Bromophenyl)-1-(isoindolin-2-yl)ethanone

To a mixture of 2-(4-bromophenyl)acetic acid (300 mg, 1.395 mmol),isoindoline (183 mg, 1.535 mmol), and HATU (796 mg, 2.093 mmol) in DMF(5 mL), was add DIEA (0.487 mL, 2.79 mmol). The mixture was stirred atrt overnight. The reaction mixture was quenched with water, thenextracted with EtOAc. The organic phase was washed with 10% LiCl, brine,and concentrated. The residue was purified via flash chromatography(EtOAc/hexane) to afford 390 mg (88%) of Intermediate 7. MS(ESI) m/z:316.0 (M+H)⁺.

Intermediate 8: (4-(2-(Isoindolin-2-yl)acetyl)phenyl)boronic acid

A mixture of Intermediate 7 (30 mg, 0.095 mmol), bis(pinacolato)diboron(24 mg, 0.095 mmol), and potassium acetate (27.9 mg, 0.285 mmol) indioxane (1 mL) was degassed (3× vacuum/Ar). Then PdCl₂(dppf) CH₂Cl₂adduct (2.083 mg, 2.85 μmol) was added, the reaction mixture wasdegassed again (3× vacuum/Ar), sealed in a vial and heated at 110° C.for 2 h. The reaction was purified via preparative HPLC to afford 14 mg(53%) of Intermediate 8. MS(ESI) m/z: 282.1 (M+H)⁺.

Intermediate 9:1-(Isoindolin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

According to a procedure similar to the preparation of Intermediate 8,Intermediate 7 (400 mg, 1.27 mmol) afforded after flash chromatography(0 to 60% EtOAc/hexane gradient) 406 mg (88%) of Intermediate 9. MS(ESI)m/z: 364.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.77 (m, J=8.3 Hz,2H), 7.39-7.33 (m, J=8.0 Hz, 2H), 7.27 (d, J=0.6 Hz, 3H), 7.27-7.24 (m,1H), 7.20 (d, J=6.6 Hz, 1H), 4.84 (s, 2H), 4.77 (s, 2H), 3.81 (s, 2H),1.38-1.31 (m, 12H).

Intermediate 10:N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoline-1-carboxamide

Intermediate 10A: N-(4-Bromophenyl)indoline-1-carboxamide

A mixture of 1-bromo-4-isocyanatobenzene (300 mg, 1.515 mmol) andindoline (199 mg, 1.667 mmol) in CH₂Cl₂ (5 mL) was stirred at rt 1 h.The reaction mixture was diluted with EtOAc (100 mL), then was washedwith 1 N HCl, sat. Na₂CO₃, and brine. The organic phase was dried overNa₂SO₄, then concentrated. The residue was purified by flashchromatography (0-60% EtOAc/hexane gradient) to afford 470 mg (98%) ofIntermediate 10A as a yellow foam. MS(ESI) m/z: 317.0 (M+H)⁺; ¹H NMR(500 MHz, CDCl₃) δ 7.88 (d, J=8.0 Hz, 1H), 7.49-7.42 (m, 2H), 7.41-7.35(m, 2H), 7.22-7.17 (m, 2H), 6.99 (td, J=7.4, 1.1 Hz, 1H), 6.47 (br. s.,1H), 4.15-4.05 (m, 2H), 3.25 (t, J=8.5 Hz, 2H).

Intermediate 10

To a mixture of Intermediate 10A (470 mg, 1.482 mmol),bis(pinacolato)diboron (452 mg, 1.778 mmol), and potassium acetate (436mg, 4.45 mmol) in dioxane (20 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct(32.5 mg, 0.044 mmol). The reaction mixture was degassed (3× vacuum/Ar),sealed in a vial and heated at 110° C. for 3 h. The reaction wasquenched with water, extracted with EtOAc (2×30 mL). The combinedorganic layer was washed with brine, dried (Na₂SO₄) and concentrated.The residue was purified by flash chromatography (0-60% EtOAc/hexanegradient) to afford 430 mg (80%) of Intermediate 10 as a white solid.MS(ESI) m/z: 365.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.89 (d, J=8.0 Hz,1H), 7.81-7.77 (m, J=8.3 Hz, 2H), 7.52-7.48 (m, 2H), 7.23-7.18 (m, 2H),7.01-6.94 (m, 1H), 6.56 (s, 1H), 4.17-4.04 (m, 2H), 3.25 (t, J=8.5 Hz,2H), 1.39-1.32 (m, 12H).

Intermediate 11: 2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoicacid

Intermediate 11A: Ethyl 2-(4-bromophenyl)propanoate

To a solution of ethyl 2-(4-bromophenyl)acetate (150 mg, 0.617 mmol) inTHF (3 mL) at −78° C., was added 1.5M LDA (0.514 mL, 0.926 mmol). Themixture was stirred at −78° C. for 20 min, then iodomethane (175 mg,1.23 mmol) was added. The solution was allowed to warm to rt and stirredovernight. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-20% EtOAc/hexane gradient) to afford120 mg (76%) of Intermediate 11A as a yellow oil. MS(ESI) m/z: 257.0(M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.47-7.42 (m, 2H), 7.21-7.16 (m, 2H),4.12 (dddd, J=17.6, 10.4, 7.1, 3.7 Hz, 2H), 3.67 (q, J=7.3 Hz, 1H), 1.48(d, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H).

Intermediate 11B: Ethyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate

To a mixture of Intermediate 11A (120 mg, 0.467 mmol),bis(pinacolato)diboron (142 mg, 0.56 mmol), and potassium acetate (137mg, 1.40 mmol) in dioxane (4 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct(10 mg, 0.014 mmol). The reaction mixture was degassed (3× vacuum/Ar),sealed and heated at 110° C. for 16 h. The reaction mixture wasconcentrated and the residue was purified by flash chromatography (0-30%EtOAc/hexane gradient) to afford 120 mg (85%) of Intermediate 11B as ayellow oil. MS(ESI) m/z: 327.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ7.81-7.75 (m, J=8.3 Hz, 2H), 7.35-7.29 (m, J=8.0 Hz, 2H), 4.11 (dddd,J=17.8, 10.6, 7.1, 3.6 Hz, 2H), 3.77-3.66 (m, 1H), 1.49 (d, J=7.2 Hz,3H), 1.37-1.30 (m, 12H), 1.19 (t, J=7.2 Hz, 3H).

Intermediate 11C: Ethyl2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoate

To 4-chlorophthalazin-1(2H)-one (70 mg, 0.388 mmol), Intermediate 11B(118 mg, 0.388 mmol) and potassium phosphate (206 mg, 0.969 mmol), wereadded dioxane (3 mL) and water (0.333 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (22.40 mg, 0.019 mmol)was added, then the mixture was degassed (2×). The reaction vial wassealed and heated in a microwave reactor at 150° C. for 30 min. Thereaction mixture was concentrated and the residue was purified by flashchromatography (0-80% EtOAc/hexane gradient) to afford 100 mg (80%) ofIntermediate 11C as a yellow foam. MS(ESI) m/z: 323.1 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 8.41-8.31 (m, 1H), 7.98-7.84 (m,2H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz,2H), 4.20-4.02 (m, 2H), 3.91 (d, J=6.9 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H),1.17 (t, J=7.0 Hz, 3H).

Intermediate 11

To a solution of Intermediate 11C (100 mg, 0.310 mmol) in THF (3 mL),was added 1M LiOH (0.620 mL, 0.620 mmol). The mixture was stirred at rtfor 3 h, then was concentrated. The residue was purified via preparativeHPLC to afford 90 mg (99%) of Intermediate 11 as a white solid. MS(ESI)m/z: 295.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.42-8.23(m, 1H), 7.99-7.82 (m, 2H), 7.78-7.66 (m, 1H), 7.61-7.52 (m, J=8.0 Hz,2H), 7.50-7.40 (m, J=8.0 Hz, 2H), 3.80 (q, J=7.2 Hz, 1H), 1.44 (d, J=6.9Hz, 3H).

Intermediate 12:6-Methoxy-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoline-1-carboxamide

Intermediate 12A: N-(4-Bromophenyl)-6-methoxyindoline-1-carboxamide

1-Bromo-4-isocyanatobenzene (146 mg, 0.737 mmol) was mixed with6-methoxyindoline (110 mg, 0.737 mmol) in DCM (3 mL), and stirred rt 2h. The reaction mixture was diluted with EtOAc (100 mL), then was washedwith 1 N HCl, sat Na₂CO₃, and brine, dried (Na₂SO₄), and concentrated.The residue was purified by flash chromatography (gradient 0-50%EtOAc/Hex) to afford Intermediate 12A (230 mg, 0.662 mmol, 90% yield) asa purple solid. MS(ESI) m/z: 346.9 (M+H)⁺; ¹H NMR (500 MHz,chloroform-d) δ 7.58 (d, J=2.2 Hz, 1H), 7.43-7.34 (m, 2H), 7.34-7.28 (m,2H), 7.02 (d, J=8.3 Hz, 1H), 6.60 (br. s., 1H), 6.50 (dd, J=8.1, 2.3 Hz,1H), 3.98 (t, J=8.5 Hz, 2H), 3.82-3.72 (m, 3H), 3.07 (t, J=8.4 Hz, 2H).

Intermediate 12

To a mixture of Intermediate 12A (230 mg, 0.662 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (202 mg,0.795 mmol), and potassium acetate (195 mg, 1.99 mmol) in dioxane (20mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (14.5 mg, 0.020 mmol). Thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 3 h. The mixture was diluted with water, extractedwith EtOAc (2×30 mL). The combined organic layer was washed with brine,dried (Na₂SO₄) and concentrated. The residue was by flash chromatography(gradient 0-60% EtOAc/Hex) to afford Intermediate 12 (230 mg, 88% yield)as a white solid. MS(ESI) m/z: 395.1 (M+H)⁺.

Intermediate 13:4-(4-Bromophenyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one

4-(4-Bromophenyl)phthalazin-1(2H)-one (1.50 g, 4.98 mmol), K₂CO₃ (1.38g, 9.96 mmol) and dry DMF (25 mL) were added into a round bottom flask.To the above mixture, 1-(chloromethyl)-4-methoxybenzene (1.35 mL, 9.96mmol) was added dropwise with stirring at rt over 5 min. Then, thereaction mixture was stirred at 50° C. for 2 h. The reaction mixture wascooled to rt, diluted with water (150 mL) and EtOAc (250 mL). Theorganic phase was separated, washed with water (3×100 mL), brine (1×50mL), and dried (Na₂SO₄). EtOAc was removed under reduced pressure andthe residue was purified by flash chromatography (0-50% EtOAc/Hex). Thematerial was recrystallized from hexanes/EtOAc (7:3; ˜100 mL), washedwith hexanes and dried to afford Intermediate 13 (1.39 g, 66.2% yield)as a white solid. MS(ESI) m/z: 421.0 (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δppm 8.56-8.49 (m, 1H), 7.75 (quind, J=7.4, 1.3 Hz, 2H), 7.69-7.62 (m,3H), 7.47 (t, J=7.9 Hz, 4H), 6.85 (d, J=8.6 Hz, 2H), 5.39 (s, 2H), 3.77(s, 3H).

Intermediate 14:4-(4-Aminophenyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one

Intermediate 13 (0.500 g, 1.187 mmol), L-proline (0.178 g, 1.543 mmol),and cuprous oxide (0.170 g, 1.19 mmol) were placed into a 20 mL pressurevial, and DMSO (8 mL) was added. The reaction mixture was degassed withstirring (3× vacuum/Ar), and sodium azide (0.154 g, 2.37 mmol) wasadded. The reaction mixture was degassed again (2× vacuum/Ar), andstirred under Ar at 100° C. for 5 h. The reaction mixture was quenchedwith sat. NH₄C₁, diluted with EtOAc (200 mL) and water (100 mL). Organicphase was washed with sat. Na₂CO₃ (2×), water, brine, dried (Na₂SO₄) andconcentrated. The product was purified via flash chromatography (0-80%EtOAc/Hex) to afford Intermediate 14 (0.386 g, 91% yield) as anoff-white solid. MS(ESI) m/z: 421.0 (M+H)⁺; ¹H-NMR (400 MHz, CDCl₃) δppm 8.54-8.46 (m, 1H), 7.84-7.77 (m, 1H), 7.77-7.66 (m, 2H), 7.50 (d,J=8.6 Hz, 2H), 7.41-7.35 (m, 2H), 6.85 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6Hz, 2H), 5.40 (s, 2H), 5.30 (s, 2H), 3.77 (s, 3H)

Intermediate 15: 1-(2-Hydroxy-2-methylpropyl)-1H-indazole-3-carboxylicacid

Intermediate 15A: Ethyl1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (75 mg, 0.39 mmol)and 2,2-dimethyloxirane (0.088 mL, 0.99 mmol), was added acetonitrile(1.5 mL). To this mixture was added Cs₂CO₃ (193 mg, 0.591 mmol). Thevial was sealed and the mixture was stirred at 90° C. for 2.5 h. Thereaction mixture was partitioned between EtOAc and H₂O. The aqueousphase was extracted with EtOAc. The combined organic phase was washedwith brine, dried (Na₂SO₄) and concentrated. The crude product waspurified by flash chromatography (gradient from 0 to 100% ethylacetate/hexanes) to afford Intermediate 15A (45 mg, 43.5% yield) as acolorless oil. MS(ESI) m/z: 263.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d)δ 8.24 (dt, J=8.3, 0.9 Hz, 1H), 7.58-7.52 (m, 1H), 7.50-7.43 (m, 1H),7.32 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.52 (q, J=7.2 Hz, 2H), 4.45 (s,2H), 2.73 (s, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.26 (s, 6H).

Intermediate 15

To a solution of Intermediate 15A (45 mg, 0.17 mmol) in THF (1 mL), wasadded 1M aq. LiOH (0.20 mL, 0.20 mmol), followed by MeOH (0.3 mL). Thehomogeneous mixture was stirred at rt for 1.5 h. Additional 1M aq. LiOH(0.1 mL, 0.1 mmol) was added and the mixture was stirred at rt for 14 h.The reaction mixture was partially evaporated to remove volatilesolvents. The solution was diluted with H₂O, then was acidified with 1 NHCl (˜0.3 mL). The aqueous phase was extracted with EtOAc (3×). Thecombined organic phase was washed with brine, dried (Na₂SO₄) andconcentrated to afford Intermediate 15 (40 mg, 100% yield) as anoff-white solid. MS(ESI) m/z: 235.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.27 (d, J=8.1 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.48 (t,J=7.6 Hz, 1H), 7.41-7.31 (m, 1H), 4.48 (s, 2H), 1.30 (s, 6H).

Intermediate 16: 1-(2-Hydroxy-2-methylpropyl)-1H-indole-3-carboxylicacid

Intermediate 16A: Methyl1-(2-hydroxy-2-methylpropyl)-1H-indole-3-carboxylate

To a vial containing methyl 1H-indole-3-carboxylate (200 mg, 1.14 mmol)and 2,2-dimethyloxirane (0.254 mL, 2.85 mmol), was added acetonitrile (3mL). To this mixture was added Cs₂CO₃ (558 mg, 1.71 mmol). The vial wassealed and the mixture was stirred at 90° C. for 2.5 h. The reactionmixture was partitioned between EtOAc and H₂O. The aqueous phase wasextracted with EtOAc. The combined organic phase was washed with brine,dried (Na₂SO₄) and concentrated. The crude product was purified by flashchromatography (gradient from 0 to 100% ethyl acetate/hexanes) to affordIntermediate 16A (274 mg, 1.108 mmol, 97% yield) white solid. MS(ESI)m/z: 248.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.26-8.11 (m, 1H),7.91 (s, 1H), 7.49-7.38 (m, 1H), 7.31-7.23 (m, 2H), 4.13 (s, 2H), 3.91(s, 3H), 1.48 (s, 1H), 1.29 (s, 6H).

Intermediate 16

To a solution of Intermediate 16A (272 mg, 1.10 mmol) in THF (5 mL), wasadded 1M aq. LiOH (1.2 mL, 1.2 mmol), followed by MeOH (1 mL). Thehomogeneous mixture was stirred at rt for 1.5 h. Additional 1M aq. LiOH(1.0 mL, 1.0 mmol) was added and the mixture was stirred at rt for 14 h.The reaction mixture was heated at 50° C. for 24 h, then at 60° C. for 9h. The reaction mixture was partially concentrated to remove the organicsolvent. The partially insoluble mixture was diluted with H₂O and waswashed with Et₂O. The organic phase was extracted with H₂O (2×). Thecombined aqueous phase was acidified to pH 3 with 1 N HCl, then wasextracted with EtOAc (3×). The combined organic phase was washed withbrine, dried (Na₂SO₄) and concentrated to afford Intermediate 16 (255mg, 99% yield) as an off-white solid. MS(ESI) m/z: 234.1 (M+H)⁺; ¹H NMR(400 MHz, chloroform-d) δ 8.27-8.20 (m, 1H), 8.01 (s, 1H), 7.49-7.42 (m,1H), 7.34-7.26 (m, 2H), 4.15 (s, 2H), 1.30 (s, 6H).

Intermediate 17: 1-(2-(Dimethylamino)ethyl)-1H-indazole-3-carboxylicacid

Intermediate 18: 2-(2-(Dimethylamino)ethyl)-2H-indazole-3-carboxylicacid

Intermediate 17A: Methyl1-(2-(dimethylamino)ethyl)-1H-indazole-3-carboxylate Intermediate 17B:Methyl 2-(2-(dimethylamino)ethyl)-2H-indazole-3-carboxylate

In a sealed tube, ethyl 1H-indazole-3-carboxylate (50 mg, 0.263 mmol)mixed with 2-bromo-N,N-dimethylethanamine (120 mg, 0.789 mmol), K₂CO₃(182 mg, 1.314 mmol) in DMF (5 mL), stirred 80° C. o/n. Concentrated andpurified by prep HPLC. Two fractions were collected, 1st fractionconcentrated to afford Intermediate 17A (29 mg, 45% yield) as a whitesolid. MS(ESI) m/z: 248.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.21(d, J=8.4 Hz, 1H), 7.65-7.59 (m, 1H), 7.58-7.52 (m, 1H), 7.43-7.36 (m,1H), 4.96 (t, J=6.4 Hz, 2H), 4.06 (s, 3H), 3.81 (t, J=6.4 Hz, 2H), 2.88(s, 6H).

2nd fraction concentrated to afford Intermediate 17B (19 mg, 29% yield)as a white solid. MS(ESI) m/z: 248.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.00 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.8 Hz, 1H),7.44-7.38 (m, 1H), 7.38-7.29 (m, 1H), 5.35 (t, J=6.1 Hz, 2H), 4.06 (s,3H), 3.80 (t, J=6.1 Hz, 2H), 3.00 (s, 6H).

Intermediate 17

Intermediate 17A (28 mg, 0.113 mmol), dissolved in THF (2 mL), add 1Mlithium hydroxide (0.283 mL, 0.283 mmol), stirred rt o/n. Concentratedand acidified with TFA, dissolved in ACN, purified via prep HPLC toafford Intermediate 17 (23 mg, 87% yield). MS(ESI) m/z: 234.1 (M+H)⁺; ¹HNMR (400 MHz, methanol-d₄) δ 8.20 (dt, J=8.3, 0.9 Hz, 1H), 7.79-7.73 (m,1H), 7.57 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.40 (ddd, J=8.1, 7.1, 0.9 Hz,1H), 4.97-4.91 (m, 2H), 3.89-3.81 (m, 2H), 3.04 (s, 6H).

Intermediate 18

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 17b (19 mg) with lithium hydroxideafforded Intermediate 18 (16 mg, 89%). MS(ESI) m/z: 234.1; ¹H NMR (400MHz, methanol-d₄) δ 8.10 (dt, J=8.5, 1.0 Hz, 1H), 7.76 (dt, J=8.7, 0.9Hz, 1H), 7.41 (ddd, J=8.6, 6.7, 1.2 Hz, 1H), 7.34-7.28 (m, 1H),5.38-5.32 (m, 2H), 3.89-3.81 (m, 2H), 3.02 (s, 6H).

Intermediate 19: 2-(Oxetan-3-ylmethyl)-2H-indazole-3-carboxylic acid

Intermediate 20: 1-(Oxetan-3-ylmethyl)-1H-indazole-3-carboxylic acid

Intermediate 19A: Ethyl 2-(oxetan-3-ylmethyl)-2H-indazole-3-carboxylateIntermediate 19B: Ethyl 1-(oxetan-3-ylmethyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (50 mg, 0.263 mmol)in acetonitrile (2 mL), were added 3-(bromomethyl)oxetane (59.5 mg,0.394 mmol) and Cs₂CO₃ (128 mg, 0.394 mmol). The vial was sealed and themixture was stirred at 90° C. for 3 h. Add DCM, filtered, concentratedand the residue was loaded onto 10 g column, eluted with EtOAc/Hex(0-60%); collected 1st peak at 20% EtOAc, concentrated to affordIntermediate 19A (27 mg, 40% yield). MS(ESI) m/z: 261.1 (M+H)⁺; ¹H NMR(400 MHz, chloroform-d) δ 8.03 (dt, J=8.4, 1.2 Hz, 1H), 7.77 (dt, J=8.5,1.0 Hz, 1H), 7.40-7.33 (m, 1H), 7.33-7.28 (m, 1H), 5.24 (d, J=7.3 Hz,2H), 4.81 (dd, J=7.9, 6.4 Hz, 2H), 4.67 (t, J=6.3 Hz, 2H), 4.50 (q,J=7.0 Hz, 2H), 3.80-3.64 (m, 1H), 1.51 (t, J=7.0 Hz, 3H).

Collected 2nd peak at 35% EtOAc was concentrated to afford Intermediate19B. (30 mg, 44% yield). MS(ESI) 261.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.23 (dt, J=8.3, 0.9 Hz, 1H), 7.54-7.44 (m, 2H), 7.33(ddd, J=8.1, 6.7, 1.2 Hz, 1H), 4.85-4.76 (m, 4H), 4.59-4.55 (m, 2H),4.54-4.48 (m, 2H), 3.70 (tt, J=7.5, 5.8 Hz, 1H), 1.48 (t, J=7.2 Hz, 3H).

Intermediate 19

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 19a (27 mg) with lithium hydroxideafforded Intermediate 19 (24 mg, 99%). MS(ESI) 233.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.39 (dt, J=8.6, 1.0 Hz, 1H), 7.91-7.87 (m, 2H),7.65 (ddd, J=8.5, 5.4, 2.3 Hz, 1H), 5.18 (dd, J=14.1, 8.4 Hz, 1H), 4.97(dd, J=13.9, 5.3 Hz, 1H), 4.90 (dd, J=11.6, 8.3 Hz, 1H), 4.69 (dd,J=11.6, 5.2 Hz, 1H), 3.86 (d, J=5.3 Hz, 2H), 3.69 (tt, J=8.3, 5.3 Hz,1H).

Intermediate 20

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 19b (30 mg) with lithium hydroxideafforded Intermediate 20 (22 mg, 82%). MS(ESI) 233.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.15 (dt, J=8.2, 1.0 Hz, 1H), 7.71 (dt, J=8.5, 0.8Hz, 1H), 7.49 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.32 (ddd, J=8.1, 7.1, 0.9Hz, 1H), 4.93-4.85 (m, 2H), 4.61 (t, J=6.2 Hz, 2H), 3.76-3.60 (m, 1H).

Intermediate 21:1-((1-((Benzyloxy)carbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxylicacid

Intermediate 21A: Methyl1-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (100 mg, 0.526mmol) in acetonitrile (5 mL), were added benzyl4-(bromomethyl)piperidine-1-carboxylate (246 mg, 0.789 mmol) and Cs₂CO₃(257 mg, 0.789 mmol). The vial was sealed and the mixture was stirred at90° C. for 12 h. Concentrated and purified by prep HPLC. Two fractionswere collected, 1st fraction concentrated to afford Intermediate 21a (80mg, 37% yield) as a white solid. MS(ESI) 408.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 9.62 (br. s., 1H), 8.24 (dt, J=8.1, 0.9 Hz, 1H),7.51-7.43 (m, 2H), 7.40-7.30 (m, 6H), 5.17-5.10 (m, 2H), 4.36 (d, J=7.3Hz, 2H), 4.30-4.15 (m, 2H), 4.06 (s, 3H), 2.86-2.66 (m, 2H), 2.30 (ddt,J=15.4, 7.8, 3.8 Hz, 1H), 1.67-1.50 (m, 2H), 1.30 (qd, J=12.4, 4.1 Hz,2H).

Intermediate 21

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 21A (80 mg) with lithium hydroxideafforded Intermediate 21 (46 mg, 60%). MS(ESI) 394.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.15 (dt, J=8.2, 1.0 Hz, 1H), 7.65 (d, J=8.6 Hz,1H), 7.46 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.34-7.24 (m, 6H), 4.87 (br.s., 2H), 4.38 (d, J=7.3 Hz, 2H), 4.11 (d, J=13.6 Hz, 2H), 2.76 (br. s.,2H), 2.25 (ddt, J=15.2, 7.7, 3.9 Hz, 1H), 1.52 (d, J=11.4 Hz, 2H), 1.25(qd, J=12.4, 4.4 Hz, 2H).

Intermediate 22:1-((Tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 22A: Methyl1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (150 mg, 0.789mmol) in DMF (2 mL), were added 4-(bromomethyl)tetrahydro-2H-pyran (212mg, 1.18 mmol) and Cs₂CO₃ (385 mg, 1.18 mmol). The vial was sealed andthe mixture was stirred at 90° C. for 3 h. The reaction mixture wasconcentrated and purified by prep HPLC. Two fractions were collected, 1st fraction was concentrated to afford Intermediate 22A (76 mg, 35%yield) as a white solid. MS(ESI) 275.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.23 (dt, J=8.3, 0.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.34(ddd, J=8.1, 4.6, 3.2 Hz, 1H), 4.37 (d, J=7.5 Hz, 2H), 4.09-3.99 (m,5H), 3.47-3.33 (m, 2H), 2.46-2.30 (m, 1H), 1.55-1.45 (m, 4H).

Intermediate 22

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 22A (78 mg) with lithium hydroxideafforded Intermediate 22 (66 mg, 89%). MS(ESI) 261.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.21-8.11 (m, 1H), 7.66 (d, J=8.6 Hz, 1H), 7.46 (td,J=7.7, 0.9 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, 1H), 4.37 (d, J=7.3Hz, 2H), 3.88 (dt, J=11.3, 3.2 Hz, 2H), 3.39-3.33 (m, 2H), 2.29 (dt,J=15.1, 7.6 Hz, 1H), 1.48-1.36 (m, 4H).

Intermediate 23:1-((3-Methyloxetan-3-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 23A: Ethyl1-((3-methyloxetan-3-yl)methyl-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (200 mg) with3-(bromomethyl)-3-methyloxetane afforded Intermediate 23A (183 mg, 63%).MS(ESI) 275.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.26-8.20 (m,1H), 7.49-7.44 (m, 2H), 7.35-7.28 (m, 1H), 4.80 (d, J=6.2 Hz, 2H), 4.65(s, 2H), 4.56-4.47 (m, 2H), 4.45-4.36 (m, 2H), 1.48 (t, J=7.2 Hz, 3H),1.30 (s, 3H).

Intermediate 23

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 23A (183 mg) with lithium hydroxide toafforded Intermediate 23 (145 mg, 88%). MS(ESI) 247.1 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.16 (dt, J=8.3, 1.0 Hz, 1H), 7.66 (d, J=8.6Hz, 1H), 7.46 (ddd, J=8.4, 7.1, 1.0 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.9Hz, 1H), 4.83 (d, J=6.2 Hz, 2H), 4.69 (s, 2H), 4.38 (d, J=6.2 Hz, 2H),1.22 (s, 3H).

Intermediate 24:1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 24A: Ethyl1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (200 mg)3-(bromomethyl)tetrahydrofuran afforded Intermediate 24A (140 mg, 49%).MS(ESI) 275.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.23 (dt, J=8.2,1.0 Hz, 1H), 7.52-7.41 (m, 2H), 7.35-7.28 (m, 1H), 4.53 (q, J=7.1 Hz,2H), 4.45 (d, J=7.7 Hz, 2H), 3.97 (td, J=8.4, 5.5 Hz, 1H), 3.80-3.70 (m,2H), 3.67-3.58 (m, 1H), 3.14-3.00 (m, 1H), 2.01 (dtd, J=12.9, 7.9, 5.6Hz, 1H), 1.80-1.67 (m, 1H), 1.49 (t, J=7.2 Hz, 3H).

Intermediate 24

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 24A (140 mg) with lithium hydroxideafforded Intermediate 24 (120 mg, 95%). MS(ESI) 247.1 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.11 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H),7.39 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.28-7.19 (m, 1H), 4.40 (d, J=7.5Hz, 2H), 3.86 (td, J=8.1, 5.5 Hz, 1H), 3.70-3.61 (m, 2H), 3.56 (dd,J=8.9, 5.4 Hz, 1H), 2.94-2.82 (m, 1H), 2.00-1.84 (m, 1H), 1.75-1.58 (m,1H).

Intermediate 25:1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid(enantiomer 1)

Intermediate 26:1-((Tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid(enantiomer 2)

The enantiomers of Intermediate 24 (64 mg) were separated via thefollowing conditions:

Column: CHIRALPAK® AD-H, 4.6×250 mm, 5 t

Mobile Phase: 15% MeOH/85% CO₂

Flow Conditions: 2.0 mL/min, 150 Bar, 35° C.

Detector Wavelength: 220 nm

Injection Details: 10 μL of ˜1 mg/mL in MeOH

1st isomer: Intermediate 25 (24 mg, 38%). MS(ESI) 247.2 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.16 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H),7.48 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.4 Hz, 1H), 4.49 (d, J=7.7 Hz, 2H),3.93 (td, J=8.1, 5.5 Hz, 1H), 3.82-3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2Hz, 1H), 3.05-2.86 (m, 1H), 2.12-1.90 (m, 1H), 1.87-1.66 (m, 1H).

2nd isomer: Intermediate 26 (25 mg, 39%). MS(ESI) 247.2 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.16 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H),7.48 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.4 Hz, 1H), 4.49 (d, J=7.7 Hz, 2H),3.93 (td, J=8.1, 5.5 Hz, 1H), 3.82-3.71 (m, 2H), 3.62 (dd, J=8.9, 5.2Hz, 1H), 3.05-2.86 (m, 1H), 2.12-1.90 (m, 1H), 1.87-1.66 (m, 1H).

Intermediate 27: 1-(Oxetan-2-ylmethyl)-1H-indazole-3-carboxylic acid

Intermediate 27A: Ethyl 1-(oxetan-2-ylmethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (160 mg) with2-(bromomethyl)oxetane afforded Intermediate 27A (100 mg, 46%). MS(ESI)247.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.21 (dt, J=8.3, 0.9 Hz,1H), 7.66 (dt, J=8.5, 0.8 Hz, 1H), 7.43 (ddd, J=8.4, 7.0, 1.1 Hz, 1H),7.36-7.27 (m, 1H), 5.33-5.21 (m, 1H), 4.82-4.66 (m, 2H), 4.64-4.48 (m,3H), 4.23 (dt, J=9.1, 6.0 Hz, 1H), 2.80-2.64 (m, 1H), 2.64-2.46 (m, 1H),1.48 (t, J=7.2 Hz, 3H).

Intermediate 27

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 27A (100 mg) with lithium hydroxideafforded Intermediate 27 (90 mg, 99%). MS(ESI) 233.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.14 (dt, J=8.3, 1.0 Hz, 1H), 7.80-7.69 (m, 1H),7.44 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.37-7.25 (m, 1H), 5.25 (dtd, J=7.7,6.4, 3.7 Hz, 1H), 4.81-4.64 (m, 2H), 4.55 (ddd, J=8.6, 7.3, 5.7 Hz, 1H),4.28 (dt, J=9.1, 6.0 Hz, 1H), 2.74 (dtd, J=11.4, 8.2, 6.3 Hz, 1H),2.61-2.51 (m, 1H).

Intermediate 28: 1-(2-Methoxyethyl)-1H-indazole-3-carboxylic acid

Intermediate 28A: Ethyl 1-(2-methoxyethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with1-bromo-2-methoxyethane afforded Intermediate 28A (104 mg, 53%). MS(ESI)249.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.20 (dt, J=8.2, 1.0 Hz,1H), 7.55 (d, J=8.6 Hz, 1H), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.29(ddd, J=8.0, 7.0, 0.8 Hz, 1H), 4.63 (t, J=5.5 Hz, 2H), 4.52 (q, J=7.0Hz, 2H), 3.85 (t, J=5.4 Hz, 2H), 3.26 (s, 3H), 1.48 (t, J=7.0 Hz, 3H).

Intermediate 28

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 28A (104 mg) with lithium hydroxideafforded Intermediate 28 (90 mg, 98%). MS(ESI) 221.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.14 (dt, J=8.3, 0.9 Hz, 1H), 7.67 (dt, J=8.6, 0.9Hz, 1H), 7.45 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.8Hz, 1H), 4.64 (t, J=5.2 Hz, 2H), 3.85 (t, J=5.3 Hz, 2H), 3.27-3.20 (m,3H).

Intermediate 29: 1-(2-Hydroxypropyl)-1H-indazole-3-carboxylic acid

Intermediate 29A: Methyl 1-(2-hydroxypropyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (200 mg, 1.052mmol) in DMF (3 mL), was added 2-methyloxirane (122 mg, 2.103 mmol) andCs₂CO₃ (411 mg, 1.262 mmol). The vial was sealed and the mixture wasstirred at 80° C. o/n. LC/MS showed reaction completed. Quenched withwater, extracted with EtOAc, washed organic layer with 10% LiCl, brine,concentrated and the residue was purified by prep HPLC to affordIntermediate 29A (35 mg, 14%). MS(ESI) 235.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.19 (dt, J=8.2, 1.0 Hz, 1H), 7.95 (s, 1H), 7.58-7.52(m, 1H), 7.43 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.0, 6.9, 0.9Hz, 1H), 4.50-4.35 (m, 3H), 4.03-3.94 (m, 3H), 2.93 (s, 2H), 2.85 (d,J=0.4 Hz, 2H), 1.37-1.24 (m, 3H).

Intermediate 29

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 29A (35 mg) with lithium hydroxideafforded Intermediate 29 (25 mg, 81%). MS(ESI) 221.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.15 (dt, J=8.2, 1.0 Hz, 1H), 7.73-7.65 (m, 1H),7.46 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.1, 7.0, 0.8 Hz, 1H),4.48-4.42 (m, 2H), 4.29 (td, J=6.4, 5.4 Hz, 1H), 1.28-1.18 (m, 3H).

Intermediate 30:1-(3-(Benzyloxy)-2-hydroxypropyl)-1H-indazole-3-carboxylic acid

To a vial containing ethyl 1H-indazole-3-carboxylate (200 mg, 1.052mmol) in DMF (3 mL), was added 2-((benzyloxy)methyl)oxirane (345 mg,2.103 mmol) and Cs₂CO₃ (514 mg, 1.577 mmol). The vial was sealed and themixture was stirred at 80° C. o/n. LC/MS showed reaction completed.Quenched with water, extracted with EtOAc, washed organic layer with 10%LiCl, brine, concentrated and the residue was purified by prep HPLC. 1stfraction concentrated to afford Intermediate 30 (120 mg, 35% yield) as awhite solid. MS(ESI) 327.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.19(d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.46-7.37 (m, 1H), 7.36-7.27(m, 6H), 4.63-4.57 (m, 2H), 4.51-4.48 (m, 2H), 4.45-4.36 (m, 1H),3.59-3.41 (m, 4H).

Intermediate 31: 1-(2,3-Dihydroxypropyl)-1H-indazole-3-carboxylic acid

Intermediate 30 (90 mg, 0.276 mmol) was dissolved in MeOH (3 mL),degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon for 3 h,filtered and concentrated under vacuum to afford Intermediate 31 as acolorless oil (58 mg, 89%). MS(ESI) 237.1 (M+H)⁺; ¹H NMR (400 MHz,methanol-d₄) δ 8.17-8.10 (m, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.45 (ddd,J=8.4, 7.1, 1.0 Hz, 1H), 7.29 (ddd, J=8.0, 7.0, 0.8 Hz, 1H), 4.62 (dd,J=14.3, 4.4 Hz, 1H), 4.51 (dd, J=14.3, 7.3 Hz, 1H), 4.16 (dq, J=7.3, 5.0Hz, 1H), 3.66-3.53 (m, 2H).

Intermediate 32: 1-(2-(2-Methoxyethoxy)ethyl)-1H-indazole-3-carboxylicacid

Intermediate 32A: Ethyl1-(2-(2-methoxyethoxy)ethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with1-bromo-2-(2-methoxyethoxy)ethane afforded Intermediate 32A (105 mg,46%). MS(ESI) 293.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.20 (dt,J=8.2, 1.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.42 (ddd, J=8.4, 7.0, 1.1 Hz,1H), 7.30 (ddd, J=8.1, 7.0, 0.9 Hz, 1H), 4.67 (t, J=5.6 Hz, 2H), 4.53(q, J=7.3 Hz, 2H), 3.97 (t, J=5.7 Hz, 2H), 3.56-3.48 (m, 2H), 3.43-3.37(m, 2H), 3.28 (s, 3H), 1.48 (t, J=7.2 Hz, 3H).

Intermediate 32

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 32A (105 mg)) with lithium hydroxideafforded Intermediate 32 (93 mg, 98%). MS(ESI) 265.1 (M+H)⁺; ¹H NMR (500MHz, methanol-d₄) δ 8.12 (dt, J=8.2, 0.9 Hz, 1H), 7.72-7.62 (m, 1H),7.42 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.27 (ddd, J=8.1, 7.0, 0.8 Hz, 1H),4.62 (t, J=5.4 Hz, 2H), 3.93 (t, J=5.4 Hz, 2H), 3.49-3.43 (m, 2H),3.37-3.32 (m, 2H), 3.17 (s, 3H).

Intermediate 33:1-((1-(tert-Butoxycarbonyl)azetidin-3-yl)methyl)-1H-indazole-3-carboxylicacid

Intermediate 33A: Ethyl1-((1-(tert-butoxycarbonyl)azetidin-3-yl)methyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with tert-butyl3-(bromomethyl)azetidine-1-carboxylate afforded Intermediate 33A (180mg, 48%). MS(ESI) 360.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.22(d, J=8.4 Hz, 1H), 7.56-7.43 (m, 2H), 7.32 (ddd, J=8.0, 6.8, 1.1 Hz,1H), 4.67 (d, J=7.7 Hz, 2H), 4.57-4.44 (m, 2H), 4.02 (t, J=8.5 Hz, 2H),3.80 (dd, J=8.9, 5.2 Hz, 2H), 3.24 (ddd, J=7.9, 5.1, 2.6 Hz, 1H), 1.48(t, J=7.0 Hz, 3H), 1.44 (s, 9H).

Intermediate 33

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 33A (180 mg) with lithium hydroxideafforded Intermediate 33 (155 mg, 93%). MS(ESI) 332.1 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.16 (dt, J=8.2, 1.0 Hz, 1H), 7.73 (d, J=8.6Hz, 1H), 7.50 (ddd, J=8.5, 7.2, 1.1 Hz, 1H), 7.33 (ddd, J=8.0, 7.0, 0.8Hz, 1H), 4.72 (d, J=7.3 Hz, 2H), 4.06-3.96 (m, 2H), 3.84 (br. s., 2H),3.27-3.17 (m, 1H), 1.41 (s, 9H).

Intermediate 34: 1-(2-(Benzyloxy)ethyl)-1H-indazole-3-carboxylic acid

Intermediate 34A: Ethyl 1-(2-(benzyloxy)ethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with((2-bromoethoxy)methyl)benzene afforded Intermediate 34A (120 mg, 59%).MS(ESI) 325.2 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ 8.21 (d, J=8.3Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 7.32-7.27 (m,1H), 7.25-7.20 (m, 3H), 7.11-7.06 (m, 2H), 4.66 (t, J=5.5 Hz, 2H), 4.52(q, J=7.2 Hz, 2H), 4.40 (s, 2H), 3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0Hz, 3H).

Intermediate 34

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 34A (120 mg) with lithium hydroxideafforded Intermediate 34 (100 mg, 91%). MS(ESI) 297.2 (M+H)⁺; ¹H NMR(500 MHz, methanol-d₄) δ 8.15 (dt, J=8.1, 1.0 Hz, 1H), 7.65 (d, J=8.5Hz, 1H), 7.42 (ddd, J=8.5, 7.1, 1.0 Hz, 1H), 7.33-7.25 (m, 1H),7.20-7.13 (m, 3H), 7.05-6.90 (m, 2H), 4.65 (t, J=5.2 Hz, 2H), 4.37 (s,2H), 3.91 (t, J=5.1 Hz, 2H).

Intermediate 35: 1-(2-Hydroxyethyl)-1H-indazole-3-carboxylic acid

Intermediate 34 (84 mg, 0.283 mmol) was dissolved in MeOH (2 mL),degassed and add 10% Pd/C (15 mg), stirred under H2 balloon for 2 h.Filtered and concentrated to afford Intermediate 35 (55 mg, 94%) as awhite solid. MS(ESI) 207.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.14(dt, J=8.3, 1.0 Hz, 1H), 7.72-7.62 (m, 1H), 7.45 (ddd, J=8.4, 7.0, 1.1Hz, 1H), 7.29 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 4.64-4.53 (m, 2H),4.07-3.97 (m, 2H).

Intermediate 36:1-(2-(Tetrahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxylic acid

Intermediate 36A: Ethyl1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with4-(2-bromoethyl)tetrahydro-2H-pyran afforded Intermediate 36A (90 mg,47%). MS(ESI) 303.2 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ 8.23 (dt,J=8.3, 1.0 Hz, 1H), 7.54-7.42 (m, 2H), 7.31 (ddd, J=8.0, 5.9, 1.8 Hz,1H), 4.62-4.43 (m, 4H), 4.01-3.87 (m, 2H), 3.34 (td, J=11.8, 2.1 Hz,2H), 1.98-1.85 (m, 2H), 1.65 (dd, J=12.9, 1.9 Hz, 2H), 1.54 (dd, J=7.4,3.6 Hz, 1H), 1.48 (t, J=7.2 Hz, 3H), 1.41-1.29 (m, 2H).

Intermediate 36

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 36A (90 mg) with lithium hydroxideafforded Intermediate 36 (80 mg, 98%). MS(ESI) 275.2 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.22-8.12 (m, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.45(ddd, J=8.4, 7.0, 0.9 Hz, 1H), 7.30 (ddd, J=8.1, 7.1, 0.7 Hz, 1H), 4.51(t, J=7.3 Hz, 2H), 3.96-3.81 (m, 2H), 3.38-3.24 (m, 2H), 1.86 (q, J=7.0Hz, 2H), 1.72-1.60 (m, 2H), 1.54-1.42 (m, 1H), 1.37-1.24 (m, 2H).

Intermediate 37: 1-(3-(Benzyloxy)propyl)-1H-indazole-3-carboxylic acid

Intermediate 37A: Ethyl1-(3-(benzyloxy)propyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (120 mg) with((3-bromopropoxy)methyl)benzene afforded Intermediate 37A (105 mg, 49%).MS(ESI) 339.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.22 (dt, J=8.1,1.0 Hz, 1H), 7.53-7.47 (m, 1H), 7.43-7.37 (m, 1H), 7.37-7.25 (m, 6H),4.66-4.60 (m, 2H), 4.56-4.48 (m, 2H), 4.43 (s, 2H), 3.40 (t, J=5.7 Hz,2H), 2.35-2.21 (m, 2H), 1.48 (t, J=7.2 Hz, 3H).

Intermediate 37

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 37A (105 mg) with lithium hydroxideafforded Intermediate 37 (88 mg, 91%). MS(ESI) 339.2 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.15 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.38(ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.31-7.20 (m, 7H), 4.54 (t, J=6.7 Hz,2H), 4.34 (s, 2H), 3.41-3.36 (m, 2H), 2.25-2.10 (m, 2H).

Intermediate 38: 1-(3-Hydroxypropyl)-1H-indazole-3-carboxylic acid

Intermediate 37 (80 mg, 0.258 mmol) was dissolved in MeOH (3 mL),degassed and add 10% Pd/C (20 mg). Stirred under H2 balloon for 3 h,filtered and concentrated under vacuum to afford Intermediate 38 as acolorless oil (50 mg, 75%). MS(ESI) 221.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 8.17-8.13 (m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.46 (ddd,J=8.4, 7.0, 1.1 Hz, 1H), 7.30 (ddd, J=8.0, 7.1, 0.8 Hz, 1H), 4.60 (t,J=6.9 Hz, 2H), 3.55 (t, J=6.1 Hz, 2H), 2.14 (t, J=6.3 Hz, 2H).

Intermediate 39: 1-(3-Methoxypropyl)-1H-indazole-3-carboxylic acid

Intermediate 39A: Ethyl 1-(3-methoxypropyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (80 mg) with1-bromo-3-methoxypropane afforded Intermediate 39A (50 mg, 45%). MS(ESI)263.2 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ 8.21 (d, J=8.3 Hz, 1H),7.56 (d, J=8.5 Hz, 1H), 7.40 (d, J=1.4 Hz, 1H), 7.32-7.27 (m, 1H),7.25-7.20 (m, 3H), 7.11-7.06 (m, 2H), 4.66 (t, J=5.5 Hz, 2H), 4.52 (q,J=7.2 Hz, 2H), 4.40 (s, 2H), 3.93 (t, J=5.4 Hz, 2H), 1.47 (t, J=7.0 Hz,3H).

Intermediate 39

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 39A (50 mg) with lithium hydroxideafforded Intermediate 39 (44 mg, 99%). MS(ESI) 235.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.14 (dt, J=8.3, 0.9 Hz, 1H), 7.62 (d, J=8.6 Hz,1H), 7.49-7.41 (m, 1H), 7.29 (ddd, J=8.1, 7.0, 0.8 Hz, 1H), 4.61-4.54(m, 2H), 3.28 (t, J=5.9 Hz, 2H), 3.25 (s, 3H), 2.16 (t, J=6.1 Hz, 2H).

Intermediate 40: 1-(Pyridin-4-ylmethyl)-1H-indazole-3-carboxylic acid

Intermediate 40A: Ethyl 1-(pyridin-4-ylmethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with4-(bromomethyl)pyridine afforded Intermediate 40A (50 mg, 48%). MS(ESI)282.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.61-8.42 (m, 2H), 8.26(dt, J=8.2, 1.1 Hz, 1H), 7.47-7.37 (m, 1H), 7.35-7.31 (m, 1H), 7.31 (d,J=0.7 Hz, 1H), 7.06-6.99 (m, 2H), 5.70 (s, 2H), 4.54 (q, J=7.3 Hz, 2H),1.48 (t, J=7.2 Hz, 3H).

Intermediate 40

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 40A (50 mg) with lithium hydroxideafforded Intermediate 40 (45 mg, 95%). MS(ESI) 254.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.56-8.44 (m, 2H), 8.28-8.13 (m, 1H), 7.70-7.57 (m,1H), 7.48 (d, J=1.3 Hz, 1H), 7.36 (dd, J=8.3, 1.0 Hz, 1H), 7.26-7.15 (m,2H), 5.84 (s, 2H).

Intermediate 41: 1-(Pyridin-2-ylmethyl)-1H-indazole-3-carboxylic acid

Intermediate 41A: Ethyl 1-(pyridin-2-ylmethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with2-(bromomethyl)pyridine afforded Intermediate 41A (88 mg, 85%). MS(ESI)282.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.61-8.54 (m, 1H), 8.24(dt, J=8.1, 1.0 Hz, 1H), 7.55 (td, J=7.7, 1.8 Hz, 1H), 7.45 (dt, J=8.5,0.9 Hz, 1H), 7.38 (ddd, J=8.4, 6.9, 1.2 Hz, 1H), 7.35-7.29 (m, 1H),7.20-7.14 (m, 1H), 6.92 (d, J=7.9 Hz, 1H), 5.84 (s, 2H), 4.54 (q, J=7.3Hz, 2H), 1.49 (t, J=7.2 Hz, 3H).

Intermediate 41

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 41A (88 mg) with lithium hydroxideafforded Intermediate 41 (105 mg, 91%). MS(ESI) 254.1 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.67 (dd, J=5.4, 0.8 Hz, 1H), 8.21 (dt, J=8.1,1.0 Hz, 1H), 8.12 (td, J=7.8, 1.8 Hz, 1H), 7.74-7.61 (m, 2H), 7.51 (ddd,J=8.4, 7.1, 1.0 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.37 (ddd, J=8.1, 7.1,0.9 Hz, 1H), 5.99 (s, 2H).

Intermediate 42: 1-(Pyridin-3-ylmethyl)-1H-indazole-3-carboxylic acid

Intermediate 42A: Ethyl 1-(pyridin-3-ylmethyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (70 mg) with3-(bromomethyl)pyridine afforded Intermediate 42A (18 mg, 18%). MS(ESI)282.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.61 (d, J=1.8 Hz, 1H),8.54 (dd, J=4.8, 1.5 Hz, 1H), 8.25 (dt, J=8.1, 1.0 Hz, 1H), 7.54-7.47(m, 1H), 7.45-7.30 (m, 3H), 7.22 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 5.73 (s,2H), 4.55 (q, J=7.0 Hz, 2H), 1.50 (t, J=7.2 Hz, 3H).

Intermediate 42

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 42A (18 mg) with lithium hydroxideafforded Intermediate 42 (23 mg, 98%). MS(ESI) 254.1 (M+H)⁺; ¹H NMR (500MHz, methanol-d₄) δ 8.94-8.84 (m, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.49-8.37(m, 1H), 8.18 (dt, J=8.3, 0.8 Hz, 1H), 8.02-7.92 (m, 1H), 7.77 (d, J=8.5Hz, 1H), 7.52 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.36 (ddd, J=8.1, 7.2, 0.7Hz, 1H), 5.98 (s, 2H).

Intermediate 43:6-Fluoro-1-(2-methylprop-1-en-1-yl)-1H-indazole-3-carboxylic acid

Intermediate 44:6-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid

To a vial containing methyl 6-fluoro-1H-indazole-3-carboxylate (200 mg,1.030 mmol) in DMF (3 mL), were added 2,2-dimethyloxirane (0.458 mL,5.15 mmol) and Cs₂CO₃ (403 mg, 1.236 mmol). The vial was sealed and themixture was stirred at 80° C. for 3 h. Quenched with water, acidifiedwith 1 N HCl. Extracted with EtOAc, the organic layer was concentratedand loaded on 10 g column, eluted with MeOH/DCM. Collected twofractions: 1st fraction: 5% MeOH; 2nd fraction: 8% MeOH.

1st fraction afforded Intermediate 43 (26 mg, 11%). MS(ESI) 235.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 13.78 (br. s., 1H), 8.05 (dd, J=9.1,5.5 Hz, 1H), 7.55 (dt, J=9.9, 1.1 Hz, 1H), 7.44-7.32 (m, 1H), 7.21 (td,J=9.3, 2.3 Hz, 1H), 1.93 (d, J=1.1 Hz, 3H), 1.79 (d, J=1.4 Hz, 3H).

2nd fraction afforded Intermediate 44 (90 mg, 36%). MS(ESI) 253.1(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.10 (dd, J=9.0, 5.3 Hz, 1H),7.44 (dd, J=9.5, 2.0 Hz, 1H), 7.08 (td, J=9.1, 2.1 Hz, 1H), 4.39 (s,2H), 1.24 (s, 6H).

Intermediate 45:5-Fluoro-1-(2-methylprop-1-en-1-yl)-1H-indazole-3-carboxylic acid

Intermediate 46:5-Fluoro-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxylic acid

To a vial containing methyl 5-fluoro-1H-indazole-3-carboxylate (200 mg,1.03 mmol) in ACN (3 mL), were added 2,2-dimethyloxirane (0.458 mL, 5.15mmol) and Cs₂CO₃ (403 mg, 1.24 mmol). The vial was sealed and themixture was stirred at 80° C. for 3 h. Filtered, concentrated and theresidue was loaded onto 10g column, eluted with EtOAc/Hex (0-60%);collected a 1st fraction at 40% EtOAc. Then eluted with MeOH/DCM(0-10%); collected a 2nd fraction at 10% MeOH.

2nd fraction concentrated to afford Intermediate 45 (20 mg, 8%). MS(ESI)235.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 7.84-7.70 (m, 1H), 7.63(ddd, J=9.4, 2.5, 0.7 Hz, 1H), 7.29 (dt, J=3.1, 1.5 Hz, 1H), 7.21 (td,J=9.2, 2.4 Hz, 1H), 1.98 (d, J=1.3 Hz, 3H), 1.76 (d, J=1.3 Hz, 3H).

1st fraction concentrated to afford Intermediate 46A (130 mg, 48%).MS(ESI) 267.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.81-7.76 (m,1H), 7.58-7.52 (m, 1H), 7.18 (td, J=8.9, 2.4 Hz, 1H), 4.42 (s, 2H),4.02-3.97 (m, 3H), 1.26 (s, 6H).

Intermediate 46

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 46A (130 mg) with lithium hydroxideafforded Intermediate 46 (115 mg, 93%) as a white solid. MS(ESI) 253.1(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.77-7.68 (m, 2H), 7.32-7.20 (m,1H), 4.43 (s, 2H), 1.30-1.21 (m, 6H).

Intermediate 47:1-((Tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 47A: Ethyl1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (150 mg) with2-(bromomethyl)tetrahydro-2H-pyran afforded Intermediate 47A (163 mg,72%). MS(ESI) 267.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.20 (dt,J=8.2, 1.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.43 (ddd, J=8.4, 7.1, 1.2 Hz,1H), 7.31 (ddd, J=8.0, 6.9, 0.9 Hz, 1H), 4.62-4.45 (m, 4H), 4.00-3.81(m, 2H), 3.33 (td, J=11.6, 2.5 Hz, 1H), 1.91-1.80 (m, 1H), 1.68-1.59 (m,1H), 1.57-1.44 (m, 6H), 1.42-1.28 (m, 1H).

Intermediate 47

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 47A (46 mg) with lithium hydroxideafforded Intermediate 47 (30 mg, 72%) as a white solid. MS(ESI) 261.2(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.13 (dd, J=8.1, 0.9 Hz, 1H),7.75-7.62 (m, 1H), 7.52-7.40 (m, 1H), 7.40-7.25 (m, 1H), 4.59-4.41 (m,2H), 3.94-3.80 (m, 2H), 1.93-1.78 (m, 1H), 1.65 (d, J=11.7 Hz, 1H),1.59-1.42 (m, 3H), 1.41-1.26 (m, 1H).

Intermediate 48:1-(2-Hydroxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid

Intermediate 48A: Methyl1-(2-hydroxy-2-methylpropyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate

To a vial containing methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (120mg, 0.681 mmol) in DMF (3 mL), were added 2,2-dimethyloxirane (0.303 mL,3.41 mmol) and Cs₂CO₃ (266 mg, 0.817 mmol). The vial was sealed and themixture was stirred at 80° C. for 3 h. Quenched with water, extractedwith EtOAc, concentrated and the residue was loaded onto 10g column,eluted with EtOAc/Hex (0-60%); collected a fraction at 40% EtOAc.Concentrated to afford Intermediate 48A (134 mg, 79%). MS(ESI) 249.1(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.45 (dd, J=7.9, 1.5 Hz, 1H),8.33 (dd, J=4.7, 1.7 Hz, 1H), 7.99 (s, 1H), 7.24 (dd, J=7.9, 4.6 Hz,1H), 4.44 (s, 1H), 4.33 (s, 2H), 3.92 (s, 3H), 1.24 (s, 6H).

Intermediate 48

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 48A (134 mg) with lithium hydroxideafforded Intermediate 48 (127 mg, 99%) as a white solid. MS(ESI) 235.2(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.47 (dd, J=7.9, 1.5 Hz, 1H),8.29 (d, J=4.0 Hz, 1H), 8.14 (s, 1H), 7.23 (dd, J=7.9, 4.8 Hz, 1H), 4.33(s, 2H), 1.17 (s, 6H).

Intermediate 49:5-Fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 49A: Methyl5-fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (100 mg) with3-(bromomethyl)tetrahydrofuran afforded Intermediate 49A (66 mg, 46%).MS(ESI) 279.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.87-7.81 (m,1H), 7.46-7.41 (m, 1H), 7.22 (td, J=8.9, 2.4 Hz, 1H), 4.41 (d, J=7.7 Hz,2H), 4.06-4.00 (m, 3H), 3.97-3.92 (m, 1H), 3.80-3.67 (m, 2H), 3.60 (dd,J=9.1, 4.7 Hz, 1H), 3.11-2.95 (m, 1H), 2.08-1.96 (m, 1H), 1.74-1.64 (m,1H).

Intermediate 49

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 49A (68 mg) with lithium hydroxideafforded Intermediate 49 (63 mg, 98%) as a white solid. MS(ESI) 265.2(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.74-7.67 (m, 2H), 7.26 (td,J=8.9, 2.5 Hz, 1H), 4.47 (d, J=7.7 Hz, 2H), 3.92 (td, J=8.3, 5.5 Hz,1H), 3.77-3.69 (m, 2H), 3.60 (dd, J=8.8, 5.2 Hz, 1H), 3.01-2.87 (m, 1H),2.08-1.95 (m, 1H), 1.80-1.69 (m, 1H).

Intermediate 50:6-Fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 50A: Methyl6-fluoro-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxylate

According to the procedure for preparation of Intermediate 19B,alkylation of ethyl 1H-indazole-3-carboxylate (100 mg) with3-(bromomethyl)tetrahydrofuran afforded Intermediate 50A (68 mg, 47%).MS(ESI) 279.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.22-8.15 (m,1H), 7.18-7.04 (m, 2H), 4.37 (d, J=7.7 Hz, 2H), 4.03 (s, 3H), 3.96 (td,J=8.3, 5.4 Hz, 2H), 3.82-3.72 (m, 2H), 3.61 (dd, J=9.0, 4.8 Hz, 1H),3.09-2.95 (m, 1H), 2.02 (dtd, J=12.9, 8.0, 5.5 Hz, 1H), 1.74-1.63 (m,1H).

Intermediate 50

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 50A (68 mg) with lithium hydroxideafforded Intermediate 50 (50 mg, 77%) as a white solid. MS(ESI) 265.2(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.12 (dd, J=8.7, 5.1 Hz, 1H),7.44 (dd, J=9.4, 1.9 Hz, 1H), 7.10 (td, J=9.1, 2.2 Hz, 1H), 4.43 (d,J=7.7 Hz, 2H), 3.93 (td, J=8.2, 5.4 Hz, 1H), 3.84-3.71 (m, 2H), 3.61(dd, J=8.8, 5.5 Hz, 1H), 3.04-2.83 (m, 1H), 2.12-1.93 (m, 1H), 1.84-1.65(m, 1H).

Intermediate 51:6-(2-Hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 51A: Ethyl 6-hydroxypyrazolo[1,5-a]pyridine-3-carboxylic

Ethyl 6-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (130 mg, 0.59 mmol)was mixed with aluminum tribromide (787 mg, 2.95 mmol) in EtSH (2 ml)and stirred at rt for 2 h. Cooled to 0° C., add MeOH dropwise,concentrated, and the residue was loaded onto 10g column, eluted withEtOAc/Hex (0-40%); collected fraction at 30% EtOAc, concentrated toafford Intermediate 51A (50 mg, 41%). MS(ESI) 207.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.25 (s, 1H), 8.15 (dd, J=2.1, 0.8 Hz, 1H), 7.99(dd, J=9.5, 0.7 Hz, 1H), 7.27 (dd, J=9.6, 2.1 Hz, 1H), 4.35 (q, J=7.3Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).

Intermediate 51B: Ethyl6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of Intermediate 51A (50 mg, 0.24 mmol) in acetonitrile (3ml) and water (0.2 ml) was added K₂CO₃ (134 mg, 0.970 mmol) and2,2-dimethyloxirane (0.646 ml, 7.27 mmol). The reaction mixture washeated to 120° C. by MW for 35 min, LCMS shows the reaction wascompleted with formation of desired product. Filtered and purifiedthrough prep HPLC to afford Intermediate 51B (51 mg, 76%). MS(ESI) 279.2(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.35 (s, 1H), 8.34-8.31 (m,1H), 8.11-8.04 (m, 1H), 7.29 (dd, J=9.6, 2.1 Hz, 1H), 4.39 (q, J=7.2 Hz,2H), 3.86 (s, 2H), 1.45-1.39 (m, 9H)

Intermediate 51

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 51B (51 mg) with lithium hydroxideafforded Intermediate 51 (25 mg, 55%) as a white solid. MS(ESI) 251.2(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.33 (dd, J=2.2, 0.6 Hz, 1H),8.28 (s, 1H), 8.03 (dd, J=9.6, 0.6 Hz, 1H), 7.37 (dd, J=9.6, 1.9 Hz,1H), 3.86 (s, 2H), 1.35 (s, 6H)

Intermediate 52: 6-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 52A: Ethyl6-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a vial containing Intermediate 51A (30 mg, 0.145 mmol) in CH₃CN (3mL), were added 1-bromo-2-methoxyethane (30.3 mg, 0.218 mmol) and Cs₂CO₃(95 mg, 0.29 mmol). The vial was sealed and the mixture was stirred at70° C. for 3 h. LC/MS showed reaction completed. Filtered andconcentrated. The residue was loaded onto 10 g column, eluted withEtOAc/Hex (0-50%); collected fraction at 30% EtOAc, concentrated toafford Intermediate 52A (25 mg, 65%). MS(ESI) 265.2 (M+H)⁺; ¹H NMR (500MHz, methanol-d₄) δ 8.35 (dd, J=2.2, 0.5 Hz, 1H), 8.27 (s, 1H),8.03-7.99 (m, 1H), 7.34 (dd, J=9.6, 2.2 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H),4.22-4.15 (m, 2H), 3.82-3.74 (m, 2H), 3.50-3.41 (m, 3H), 1.40 (t, J=7.2Hz, 3H).

Intermediate 52

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 52A (25 mg) with lithium hydroxideafforded Intermediate 52 (12 mg, 54%) as a white solid. MS(ESI) 237.1(M+H)⁺.

Intermediate 53:6-(2-(Pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 53A: Ethyl6-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 52A,alkylation of Intermediate 51A (36 mg) with 1-(2-bromoethyl)pyrrolidineafforded Intermediate 53A (29 mg, 55%) as a white solid. MS(ESI) 304.2(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) d 8.39-8.25 (m, 3H), 8.07 (d,J=9.5 Hz, 1H), 7.21 (dd, J=9.7, 2.2 Hz, 1H), 4.44-4.38 (m, 3H),4.38-4.33 (m, 1H), 4.06-3.94 (m, 2H), 3.69-3.62 (m, 2H), 3.05 (d, J=9.7Hz, 2H), 2.17 (d, J=4.0 Hz, 4H), 1.41 (t, J=7.2 Hz, 3H).

Intermediate 53

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 53A (29 mg) with lithium hydroxideafforded Intermediate 53 (16 mg, 61%) as a white solid. MS(ESI) 276.2(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.41 (d, J=1.5 Hz, 1H), 8.30 (s,1H), 8.04 (d, J=9.5 Hz, 1H), 7.39 (dd, J=9.6, 2.1 Hz, 1H), 4.47-4.40 (m,2H), 3.80 (d, J=7.5 Hz, 2H), 3.76-3.68 (m, 2H), 3.25 (br. s., 2H),2.21-2.12 (m, 2H), 2.09 (br. s., 2H).

Intermediate 54:6-(2-(Dimethylamino)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 54A: Ethyl6-(2-(dimethylamino)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 52A,alkylation of Intermediate 51A (35 mg) with2-bromo-N,N-dimethylethanamine afforded Intermediate 54A (20 mg, 43%) asa white solid. MS(ESI) 278.2 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ8.47 (dd, J=2.2, 0.8 Hz, 1H), 8.32 (s, 1H), 8.07 (dd, J=9.6, 0.5 Hz,1H), 7.42 (dd, J=9.6, 2.2 Hz, 1H), 4.52-4.42 (m, 2H), 4.36 (q, J=7.2 Hz,2H), 3.70-3.61 (m, 2H), 3.06-2.99 (m, 6H), 1.45-1.35 (m, 3H).

Intermediate 54

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 54A (18 mg) with lithium hydroxideafforded Intermediate 54 (8 mg, 61%) as a white solid. MS(ESI) 250.2(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.47 (dd, J=2.2, 0.6 Hz, 1H),8.32 (s, 1H), 8.11-8.07 (m, 1H), 7.41 (dd, J=9.6, 2.2 Hz, 1H), 4.49-4.40(m, 2H), 3.71-3.60 (m, 2H), 3.02 (s, 6H).

Intermediate 55:6-(2-Morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 55A: Ethyl6-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 52A,alkylation of Intermediate 51A (40 mg) with 4-(2-bromoethyl)morpholineafforded Intermediate 55A (47 mg, 76%) as a white solid. MS(ESI) 320.3(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.13-8.10 (m,1H), 8.02 (dd, J=9.7, 0.7 Hz, 1H), 7.20 (dd, J=9.7, 2.2 Hz, 1H), 4.36(q, J=7.2 Hz, 2H), 4.11 (t, J=5.6 Hz, 2H), 3.77-3.69 (m, 4H), 2.83 (t,J=5.6 Hz, 2H), 2.61-2.53 (m, 4H), 1.40 (t, J=7.2 Hz, 3H).

Intermediate 55

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 55A (47 mg) with lithium hydroxideafforded Intermediate 55 (58 mg, 97%) as a white solid. MS(ESI) 320.3(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.38 (dd, J=2.2, 0.7 Hz, 1H),8.32 (s, 1H), 8.09 (dd, J=9.7, 0.7 Hz, 1H), 7.36 (dd, J=9.7, 2.2 Hz,1H), 4.51-4.43 (m, 2H), 3.97 (br. s., 4H), 3.72-3.64 (m, 2H), 3.61-3.35(m, 4H).

Intermediate 56:5-(2-Hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 56A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate

Ethyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate (300 mg, 1.36 mmol)was mixed with aluminum tribromide (1817 mg, 6.81 mmol) in EtSH (5 ml)and stirred at rt for 3 h. Cooled to 0° C., add MeOH dropwise, thenwater. Extracted with EtOAc. Concentrated and the residue was loadedonto 24 g column, eluted with EtOAc/Hex (0-40%); collected fraction at30% EtOAc, concentrated to afford Intermediate 56A (90 mg, 32%). MS(ESI)207.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.42 (dd, J=7.5, 0.4 Hz,1H), 8.21 (s, 1H), 7.41-7.27 (m, 1H), 6.67 (dd, J=7.5, 2.6 Hz, 1H), 4.32(q, J=7.0 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H).

Intermediate 56B: Ethyl5-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of Intermediate 56A (22 mg, 0.107 mmol) in acetonitrile (3ml) and water (0.2 ml) was added K₂CO₃ (59.0 mg, 0.427 mmol) and2,2-dimethyloxirane (0.142 ml, 1.600 mmol). The reaction mixture washeated to 120° C. by microwave for 30 min. Additional2,2-dimethyloxirane (0.142 ml, 1.60 mmol) was added, and the mixture wasstirred at 120° C. for 30 min. The mixture was concentrated and theresidue was loaded onto 10g column, eluted with EtOAc/Hex (0-40%);collected product at 30% EtOAc, concentrated to afford Intermediate 56B(27 mg, 91%). MS(ESI) 279.3 (M+H)⁺.

Intermediate 56

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 56B (27 mg) with lithium hydroxideafforded Intermediate 56 (19 mg, 78%) as a white solid. MS(ESI) 251.1(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.54-8.42 (m, 1H), 8.25 (s, 1H),7.42 (d, J=2.6 Hz, 1H), 6.82 (dd, J=7.5, 2.6 Hz, 1H), 3.92 (s, 2H), 1.35(s, 6H).

Intermediate 57: 5-Methoxypyrazolo[1,5-a]pyridine-3-carboxylic acid

According to the procedure for preparation of Intermediate 17,saponification of ethyl 5-methoxypyrazolo[1,5-a]pyridine-3-carboxylate(19 mg) with lithium hydroxide afforded Intermediate 57 (16 mg, 97%) asa white solid. MS(ESI) 193.1 (M+H)⁺.

Intermediate 58:5-(2-(Pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 58A: Ethyl5-(2-(pyrrolidin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a vial containing Intermediate 56A (45 mg, 0.22 mmol) in DMF (3 mL),were added 1-(2-bromoethyl)pyrrolidine, hydrobromide (85 mg, 0.33 mmol)and Cs₂CO₃ (213 mg, 0.655 mmol). The vial was sealed and the mixture wasstirred at 70° C. for 16 h. LC/MS showed reaction completed. Filteredand concentrated. Purified through prep HPLC to afford Intermediate 58A(48 mg, 73%). MS(ESI) 304.3 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.55(dd, J=7.4, 0.6 Hz, 1H), 8.30 (s, 1H), 7.52 (d, J=2.8 Hz, 1H), 6.86 (dd,J=7.7, 2.8 Hz, 1H), 4.55-4.47 (m, 2H), 4.36 (q, J=7.0 Hz, 2H), 3.84-3.73(m, 4H), 3.29-3.19 (m, 2H), 2.21 (br. s., 2H), 2.08 (br. s., 2H),1.46-1.33 (m, 3H).

Intermediate 58

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 58A (48 mg) with lithium hydroxideafforded Intermediate 58 (34 mg, 55%) as a white solid. MS(ESI) 276.3(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ ppm 8.54 (1H, dd, J=7.57, 0.69Hz), 8.29 (1H, s), 7.5 (1H, d, J=2.75 Hz), 6.85 (1H, dd, J=7.43, 2.75Hz), 4.44-4.56 (2H, m), 3.71-3.84 (4H, m),3.26-3.28 (2H, m), 2.21 (2H,br. s.), 2.07 (2H, br. s.).

Intermediate 59: 5-(2-Methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 59A: Ethyl5-(2-methoxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 58A,alkylation of Intermediate 56A (35 mg) with 1-bromo-2-methoxyethaneafforded Intermediate 59A (37 mg, 82%) as a white solid. MS(ESI) 265.3(M+H)⁺; ¹H NMR (500 MHz, chloroform-d) d 8.31 (dd, J=7.4, 0.5 Hz, 1H),8.27 (s, 1H), 7.42 (d, J=2.8 Hz, 1H), 6.66 (dd, J=7.4, 2.8 Hz, 1H), 4.35(q, J=7.0 Hz, 2H), 4.28-4.17 (m, 2H), 3.85-3.74 (m, 2H), 3.51-3.42 (m,3H), 1.39 (t, J=7.2 Hz, 3H).

Intermediate 59

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 59A (37 mg) with lithium hydroxideafforded Intermediate 59 (28 mg, 85%) as a white solid. MS(ESI) 237.3(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.47 (dd, J=7.6, 0.5 Hz, 1H),8.26 (s, 1H), 7.44 (d, J=2.6 Hz, 1H), 6.77 (dd, J=7.5, 2.6 Hz, 1H),4.31-4.19 (m, 2H), 3.90-3.75 (m, 2H), 3.47-3.39 (m, 3H).

Intermediate 60:5-(2-Morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 60A: Ethyl5-(2-morpholinoethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 58A,alkylation of Intermediate 56A (40 mg) with 4-(2-bromoethyl)morpholineafforded Intermediate 60A (51 mg, 82%) as a white solid. MS(ESI) 320.3(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.30 (dd, J=7.5, 0.7 Hz, 1H),8.25 (s, 1H), 7.40 (d, J=2.6 Hz, 1H), 6.60 (dd, J=7.5, 2.6 Hz, 1H), 4.33(q, J=7.0 Hz, 2H), 4.19 (t, J=5.6 Hz, 2H), 3.78-3.67 (m, 4H), 2.83 (t,J=5.6 Hz, 2H), 2.61-2.53 (m, 4H), 1.37 (t, J=7.2 Hz, 3H).

Intermediate 60

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 60A (51 mg) with lithium hydroxideafforded Intermediate 60 (60 mg, 93%) as a white solid. MS(ESI) 292.3(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.53 (dd, J=7.6, 0.5 Hz, 1H),8.29 (s, 1H), 7.50 (d, J=2.6 Hz, 1H), 6.83 (dd, J=7.5, 2.6 Hz, 1H),4.58-4.51 (m, 2H), 4.05 (br. s., 2H), 3.88 (br. s., 2H), 3.78-3.70 (m,2H), 3.65-3.48 (m, 2H), 3.45-3.34 (m, 2H).

Intermediate 61:5-(2-Hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 61A: Ethyl5-(2-hydroxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of Intermediate 56A (41 mg, 0.20 mmol) in acetonitrile (3ml) and water (0.2 ml) was added K₂CO₃ (137 mg, 0.994 mmol) and2-methyloxirane (0.417 ml, 5.97 mmol). The reaction mixture was heatedto 120° C. on MW for 30 min. Reaction is completed. Concentrated and theresidue was loaded onto 10 g column, eluted with EtOAc/Hex (0-50%);collected fraction at 30% EtOAc, concentrated to afford Intermediate 61A(26 mg, 50%). MS(ESI) 265.2 (M+H)⁺.

Intermediate 61

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 61A (26 mg) with lithium hydroxideafforded Intermediate 61 (21 mg, 82%) as a white solid. MS(ESI) 265.2(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.46 (dd, J=7.6, 0.6 Hz, 1H),8.27-8.23 (m, 1H), 7.41 (d, J=2.6 Hz, 1H), 6.84-6.75 (m, 1H), 4.17 (td,J=6.5, 4.0 Hz, 1H), 4.08-3.90 (m, 2H), 1.38-1.23 (m, 3H).

Intermediate 62: 5-(2-Hydroxyethoxy)pyrazolo[1,5-a]pyridine-3-carboxylicacid

Intermediate 62A: Methyl5-(2-(benzyloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

According to the procedure for preparation of Intermediate 58A,alkylation of methyl 5-hydroxypyrazolo[1,5-a]pyridine-3-carboxylate (43mg) with ((2-bromoethoxy)methyl)benzene afforded Intermediate 62A (71mg, 99%). MS(ESI) 327.3 (M+H)⁺.

Intermediate 62B:5-(2-(Benzyloxy)ethoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 62A (75 mg) with lithium hydroxideafforded Intermediate 62B (46 mg, 64%) as a white solid. MS(ESI) 313.2(M+H)⁺.

Intermediate 62

Intermediate 62B (43 mg, 0.138 mmol) was mixed with MeOH (5 mL),degassed, add 10% Pd/C (ca. 20 mg), stirred under H2 balloon o/n for 16h. Filtered and concentrated to afford Intermediate 62 (26 mg, 85%).MS(ESI) 223.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.46 (d, J=7.7 Hz,1H), 8.25 (s, 1H), 7.42 (d, J=2.6 Hz, 1H), 6.78 (dd, J=7.6, 2.8 Hz, 1H),4.25-4.14 (m, 2H), 3.97-3.87 (m, 2H).

Intermediate 63:5-(2-Hydroxy-3-methoxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylic acid

Intermediate 63A: Ethyl5-(2-hydroxy-3-methoxypropoxy)pyrazolo[1,5-a]pyridine-3-carboxylate

To a solution of Intermediate 56A (38 mg, 0.184 mmol) in acetonitrile (3ml) and water (0.2 ml) was added K₂CO₃ (102 mg, 0.737 mmol) and2-(methoxymethyl)oxirane (487 mg, 5.53 mmol). The reaction mixture washeated to 120° C. on MW for 35 min, LCMS shows the reaction was completewith formation of desired product. Filtered and purified through prepHPLC to afford Intermediate 63A (30 mg, 55%). MS(ESI) 295.2 (M+H)⁺.

Intermediate 63

According to the procedure for preparation of Intermediate 17,saponification of Intermediate 63A (60 mg) with lithium hydroxide affordIntermediate 63 (47 mg, 87%) as a white solid. MS(ESI) 267.1 (M+H)⁺; ¹HNMR (500 MHz, methanol-d₄) δ 8.48-8.45 (m, 1H), 8.26 (s, 1H), 7.43 (d,J=2.8 Hz, 1H), 6.78 (dd, J=7.4, 2.8 Hz, 1H), 4.24-4.06 (m, 3H),3.60-3.53 (m, 2H), 3.46-3.38 (m, 3H).

Intermediate 66: 4-(4-Aminophenyl)isoquinolin-1(2H)-one, TFA

To 4-bromoisoquinolin-1(2H)-one (166 mg, 0.741 mmol),(4-((tert-butoxycarbonyl)amino)phenyl)boronic acid (176 mg, 0.741 mmol)and K₃PO₄ (393 mg, 1.85 mmol), were added dioxane (9 mL) and water (1mL). The mixture was degassed (evacuated and flushed with Ar (5×)).Pd(PPh₃)₄ (43 mg, 0.037 mmol) was added, then the mixture was degassed(2×). The reaction vial was sealed and heated in a microwave reactor at150° C. for 40 min. The reaction mixture was concentrated, then theresidue was purified by flash chromatography (0-100% EtOAc/Hex). Theproduct was dissolved in DCM (2 mL), then was treated with TFA (1 mL).The mixture was stirred rt for 1 h, concentrated and purified viapreparative HPLC to afford Intermediate 66 (117 mg, 45% yield). MS(ESI)m/z: 237.1 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 8.41 (dd, J=8.0, 0.8Hz, 1H), 7.70 (ddd, J=8.3, 7.0, 1.5 Hz, 1H), 7.61-7.50 (m, 5H),7.49-7.42 (m, 2H), 7.14 (s, 1H), 3.35 (s, 1H).

Intermediate 67: 2-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)aceticacid

Intermediate 67A: Ethyl2-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)acetate

To 4-bromoisoquinolin-1(2H)-one (166 mg, 0.741 mmol), Intermediate 1A(215 mg, 0.741 mmol) and K₃PO₄ (393 mg, 1.85 mmol), were added dioxane(9 mL) and water (1 mL). The mixture was degassed (evacuated and flushedwith Ar (5×)). Pd(PPh₃)₄ (43 mg, 0.037 mmol) was added, then the mixturewas degassed (2×). The reaction vial was sealed and heated in amicrowave reactor at 150° C. for 40 min. The reaction mixture wasconcentrated, then was purified via prep HPLC to afford Intermediate 67A(21 mg, 9.2% yield). MS(ESI) m/z: 308.1 (M+H)⁺.

Intermediate 67

A solution of Intermediate 67A (21 mg, 0.068 mmol) in THF, was treatedwith 1M lithium hydroxide (0.2 ml, 0.200 mmol). The mixture was stirredrt for 16 h, then was concentrated. The residue was purified viapreparative HPLC to afford Intermediate 67 (13 mg, 68% yield). MS(ESI)m/z: 280.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.40 (br. s., 1H), 11.43(d, J=5.2 Hz, 1H), 8.30 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (ddd, J=8.1, 7.0,1.4 Hz, 1H), 7.57-7.49 (m, 2H), 7.42-7.33 (m, 5H), 7.08 (d, J=5.8 Hz,1H), 3.31 (br. s., 2H).

Intermediate 68: 4-Bromo-6,7-dimethoxyisoquinolin-1 (2H)-one

To a solution of 6,7-dimethoxyisoquinolin-1(2H)-one (205 mg, 1.00 mmol)in AcOH (2 mL), was add bromine (192 mg, 1.199 mmol) in AcOH (1 mL). Themixture was stirred rt for 1 h, then poured onto ice and extracted withEtOAc. The organic phase was washed with brine, then was concentrated.The product was purified by flash chromatography (0-80% EtOAc/Hex) toafford Intermediate 68 (230 mg, 0.81 mmol, 81% yield) as white form.MS(ESI) m/z: 283.9 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (br. s.,1H), 7.62 (s, 1H), 7.44 (br. s., 1H), 7.13 (s, 1H), 3.94 (s, 3H), 3.89(s, 3H).

Intermediate 69: 6-Isopropoxyindoline

Intermediate 69A: 6-(Benzyloxy)indoline

To a solution of 6-(benzyloxy)-1H-indole (580 mg, 2.60 mmol) in EtOH (5mL) at 0° C., was added Sodium cyanoborohydride (326 mg, 5.20 mmol). Themixture was stirred rt for 16 h then was concentrated. The residue waspurified via prep HPLC to afford Example 69A (280 mg; 32% yield) as ayellow oil. MS(ESI) m/z: 226.1 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ10.54 (br. s., 2H), 7.46-7.32 (m, 5H), 7.26 (d, J=8.5 Hz, 1H), 7.13 (d,J=2.2 Hz, 1H), 6.99 (dd, J=8.5, 2.2 Hz, 1H), 4.99 (s, 2H), 3.97-3.84 (m,2H), 3.23 (t, J=7.6 Hz, 2H).

Intermediate 69B: tert-Butyl 6-(benzyloxy)indoline-1-carboxylate

To a mixture of Intermediate 69A (270 mg, 1.20 mmol) and Boc₂O (0.334mL, 1.44 mmol) in THF at rt, was added cat. DMAP. The resulting mixturewas stirred rt for 16 h, then was concentrated and. The residue waspurified via flash chromatography (0-50% EtOAc/Hex) to affordIntermediate 69B (150 mg; 39% yield). MS(ESI) m/z: 326.1 (M+H)⁺; ¹H NMR(500 MHz, chloroform-d) δ 7.54-7.46 (m, 2H), 7.45-7.37 (m, 2H),7.36-7.31 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.1, 2.3 Hz, 1H),5.10 (s, 2H), 4.10-3.91 (m, 2H), 3.04 (t, J=8.7 Hz, 2H), 1.71-1.55 (m,9H).

Intermediate 69C: tert-Butyl 6-hydroxyindoline-1-carboxylate

To a degassed solution of Intermediate 69B (140 mg, 0.43 mmol) in MeOH(5 mL) was added 10% Pd/C (30 mg). The mixture was stirred under H2(balloon) for 4 h. The mixture was filtered and concentrated to affordIntermediate 69C (90 mg; 89% yield) as white solid. MS(ESI) m/z: 236.1(M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.32-7.12 (m, 1H), 6.93-6.85 (m,1H), 6.41-6.30 (m, 1H), 3.95-3.85 (m, 2H), 3.01-2.88 (m, 2H), 1.54 (br.s., 9H).

Intermediate 69D: tert-Butyl 6-isopropoxyindoline-1-carboxylate

Intermediate 69C (45 mg, 0.19 mmol) was mixed with 2-iodopropane (163mg, 0.956 mmol), Cs₂CO₃ (93 mg, 0.287 mmol) in DMF (3 mL). The mixturewas stirred at 80° C. for 16 h, then was concentrated. The residue waspurified via flash chromatography (0-40% EtOAc/Hex) to affordIntermediate 69D (35 mg; 66% yield) as colorless foam. MS(ESI) m/z:277.9 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.50-7.26 (m, 1H),7.01-6.95 (m, 1H), 6.46 (dd, J=8.3, 2.5 Hz, 1H), 4.50 (dt, J=11.9, 6.0Hz, 1H), 3.99-3.83 (m, 2H), 3.03-2.92 (m, 2H), 1.64-1.48 (m, 9H),1.32-1.25 (m, 6H).

Intermediate 69

Intermediate 69D (35 mg, 0.13 mmol) was mixed with TFA (0.5 mL) and DCM(1 mL), and stirred rt for 20 min. The mixture was concentrated toafford Intermediate 69 (36 mg; 99% yield) as a colorless foam. MS(ESI)m/z: 177.9 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.40-7.31 (m, 1H),7.05-6.95 (m, 2H), 4.61 (dt, J=12.1, 6.1 Hz, 1H), 3.86 (t, J=7.7 Hz,2H), 3.24 (t, J=7.7 Hz, 2H), 1.34-1.27 (m, 6H).

Intermediate 70:1-(Isoindolin-2-yl)-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

Intermediate 70A: 2-(4-Bromo-3-methylphenyl)-1-(isoindolin-2-yl)ethanone

To a solution of 2-(4-bromo-3-methylphenyl)acetic acid (200 mg, 0.87mmol), isoindoline (0.109 mL, 0.96 mmol), and DIEA (0.305 mL, 1.75 mmol)in DMF (3 mL), was add HATU (398 mg, 1.05 mmol). The mixture was stirredat rt for 19 h. The reaction mixture was diluted with EtOAc, then waswashed with H₂O, sat. Na₂CO₃ and brine. The organic phase was dried(Na₂SO₄) and concentrated. The crude product was purified by flashchromatography to afford Intermediate 70A (128 mg, 44% yield) as anoff-white solid. MS(ESI) 329.9 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ7.48 (d, J=8.1 Hz, 1H), 7.32-7.27 (m, 3H), 7.25-7.20 (m, 2H), 7.01 (dd,J=8.1, 1.8 Hz, 1H), 4.82 (d, J=5.3 Hz, 4H), 3.69 (s, 2H), 2.38 (s, 3H).

Intermediate 70

To a degassed (evacuated and flushed with Ar (3×)) mixture ofIntermediate 70A (128 mg, 0.388 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (118 mg,0.465 mmol) and potassium acetate (114 mg, 1.16 mmol) in dioxane (2 mL),was added PdCl₂(dppf) CH₂Cl₂ adduct (15.8 mg, 0.019 mmol). The mixturewas degassed (2×), then the vial was sealed and stirred at 110° C. for2.5 h. The reaction mixture was diluted with EtOAc and was washed withH₂O and brine. The organic phase was dried (Na₂SO₄), filtered through a1″ pad of SiO₂ and concentrated. The crude product was purified by flashchromatography (gradient from 0 to 100% ethyl acetate/hexanes) to affordIntermediate 70 (126 mg, 86% yield) as a yellow solid. MS(ESI) 378.1(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.73 (d, J=7.7 Hz, 1H),7.32-7.23 (m, 3H), 7.21-7.10 (m, 3H), 4.82 (s, 2H), 4.75 (s, 2H), 3.75(s, 2H), 2.52 (s, 3H), 1.32 (s, 12H).

Intermediate 71:1-(Indolin-1-yl)-2-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

According to the procedure the preparation of Intermediate 70,substituting indoline for isoindoline afforded Intermediate 71. MS(ESI)378.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.26 (d, J=7.9 Hz, 1H),7.73 (d, J=7.5 Hz, 1H), 7.23-7.07 (m, 4H), 7.04-6.96 (m, 1H), 4.01 (t,J=8.5 Hz, 2H), 3.78 (s, 2H), 3.13 (t, J=8.5 Hz, 2H), 2.52 (s, 3H), 1.33(s, 12H).

Intermediate 72:2-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(indolin-1-yl)ethanone

According to the procedure the preparation of Intermediate 5,substituting indoline for isoindoline afforded Intermediate 72. MS(ESI)382.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.24 (d, J=8.1 Hz, 1H),7.71 (dd, J=7.5, 6.6 Hz, 1H), 7.23-7.13 (m, 2H), 7.11 (d, J=7.7 Hz, 1H),7.06-6.99 (m, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.82 (s, 2H), 3.16 (t, J=8.5Hz, 2H), 1.35 (s, 12H).

Intermediate 73: 4-Bromo-6-methoxyisoquinolin-1(2H)-one

To a solution of 6-methoxyisoquinolin-1(2H)-one (112 mg, 0.639 mmol) inDMF (2 mL), was added NBS (137 mg, 0.767 mmol). The mixture was stirredat rt overnight, then was concentrated. The residue was purified viaprep HPLC to afford Intermediate 73 (120 mg, 74% yield) as white solid.MS(ESI) m/z: 253.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (br. s.,1H), 8.16 (d, J=8.8 Hz, 1H), 7.53 (d, J=4.4 Hz, 1H), 7.18 (dd, J=8.8,2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 3.99-3.87 (m, 3H).

Intermediate 74: 1-(Indolin-6-yloxy)-2-methylpropan-2-ol, TFA

Intermediate 74A: tert-Buty6-(2-hydroxy-2-methylpropoxy)indoline-1-carboxylate

To a mixture of Intermediate 69C (12 mg, 0.051 mmol) and2,2-dimethyloxirane (37 mg, 0.51 mmol) in acetonitrile (1 mL), was addedK₂CO₃ (35 mg, 0.26 mmol) in water (0.1 mL). The mixture was stirred in asealed tube at 100° C. for 3 h, then was concentrated. The residue waspurified via flash chromatography (0-40% EtOAc/Hex) to affordIntermediate 74A (12 mg, 64% yield). MS(ESI) m/z: 308.2 (M+H)⁺. ¹H NMR(500 MHz, chloroform-d) δ 7.61-7.46 (m, 1H), 7.02 (d, J=8.0 Hz, 1H),6.50 (dd, J=8.1, 2.3 Hz, 1H), 3.99 (t, J=8.3 Hz, 2H), 3.80 (s, 2H),3.07-2.96 (m, 2H), 1.59 (d, J=18.4 Hz, 9H), 1.33 (s, 6H).

Intermediate 74

Intermediate 74A (12 mg, 0.039 mmol) was stirred with TFA (0.5 mL) andDCM (0.5 mL) for 20 min, then was concentrated to afford Intermediate 74(12 mg, 96% yield). MS(ESI) m/z: 208.2 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 7.41-7.32 (m, 1H), 7.07-6.97 (m, 2H), 3.84 (t, J=7.7 Hz,2H), 3.81 (s, 2H), 3.24 (t, J=7.7 Hz, 2H), 1.32 (s, 6H).

Intermediate 75: 6-(Pyridin-3-ylmethoxy)indoline, 2TFA

Intermediate 75A: tert-Butyl6-(pyridin-3-ylmethoxy)indoline-1-carboxylate

To a solution of pyridin-3-ylmethanol (26.4 mg, 0.242 mmol),Intermediate 69C (38 mg, 0.162 mmol), and triphenylphosphine (106 mg,0.404 mmol) in THF (3 mL), was added DEAD (0.064 mL, 0.404 mmol). Thereaction was stirred at rt overnight. The mixture was purified bypreparative HPLC to afford Intermediate 75A (42 mg, 59% yield) as awhite solid. MS(ESI) m/z: 327.1 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ15.42 (br. s., 1H), 8.91 (s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 7.82 (dd, J=8.0, 5.5 Hz, 1H), 7.63 (br. s., 1H), 7.05 (d, J=8.3Hz, 1H), 6.54 (d, J=7.2 Hz, 1H), 5.23 (s, 2H), 4.00 (t, J=8.5 Hz, 2H),3.04 (t, J=8.5 Hz, 2H), 1.56 (br. s., 9H).

Intermediate 75

Intermediate 75A (45 mg, 0.102 mmol) was stirred with TFA (1 mL) and DCM(2 mL) at rt for 20 min, then was concentrated to afford Intermediate 75(47 mg, 100% yield) as a yellow oil. MS(ESI) m/z: 227.1 (M+H)⁺; ¹H NMR(500 MHz, methanol-d₄) δ 9.01 (s, 1H), 8.85 (d, J=5.5 Hz, 1H), 8.70 (d,J=8.5 Hz, 1H), 8.10 (dd, J=8.0, 5.8 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H),7.24 (d, J=2.2 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 5.40 (s, 2H),3.94-3.85 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).

Intermediate 76: 6-(Pyridin-2-ylmethoxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting pyridin-2-ylmethanol for pyridin-3-ylmethanol affordedIntermediate 76. MS(ESI) m/z: 227.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 8.82 (dd, J=5.5, 0.8 Hz, 1H), 8.48 (td, J=7.8, 1.7 Hz,1H), 8.07 (d, J=7.7 Hz, 1H), 7.98-7.82 (m, 1H), 7.46 (d, J=8.5 Hz, 1H),7.35-7.14 (m, 2H), 5.56-5.39 (m, 2H), 3.93-3.82 (m, 2H), 3.30-3.25 (m,2H).

Intermediate 77: 6-(Pyridin-4-ylmethoxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting pyridin-4-ylmethanol for pyridin-3-ylmethanol affordedIntermediate 77. MS(ESI) m/z: 227.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 8.94-8.84 (m, 2H), 8.22-8.15 (m, 2H), 7.48-7.41 (m, 1H),7.25 (d, J=2.2 Hz, 1H), 7.21 (dd, J=8.5, 2.5 Hz, 1H), 5.51 (s, 2H),3.93-3.87 (m, 2H), 3.28 (t, J=7.7 Hz, 2H).

Intermediate 78: (R)-6-((Tetrahydrofuran-3-yl)oxy)indoline, TFA

According to the procedure for the preparation of Intermediate 75,substituting (S)-tetrahydrofuran-3-ol for pyridin-3-ylmethanol affordedIntermediate 78. MS(ESI) m/z: 206.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 7.38 (d, J=8.3 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.01 (dd,J=8.5, 2.2 Hz, 1H), 5.03 (qd, J=4.0, 1.5 Hz, 1H), 4.02-3.79 (m, 6H),3.25 (t, J=7.7 Hz, 2H), 2.32-2.21 (m, 1H), 2.12-2.04 (m, 1H).

Intermediate 79: (S)-6-((Tetrahydrofuran-3-yl)oxy)indoline, TFA

According to the procedure for the preparation of Intermediate 75,substituting (R)-tetrahydrofuran-3-ol for pyridin-3-ylmethanol affordedIntermediate 79. MS(ESI) m/z: 206.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 7.40-7.35 (m, 1H), 7.08-6.97 (m, 2H), 4.05-3.81 (m, 6H),3.25 (t, J=7.7 Hz, 2H), 2.38-2.23 (m, 1H), 2.17-2.03 (m, 1H).

Intermediate 80: (R)-6-((1-Methylpyrrolidin-3-yl)oxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting (S)-1-methylpyrrolidin-3-ol for pyridin-3-ylmethanolafforded Intermediate 80. MS(ESI) m/z: 219.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 7.46-7.39 (m, 1H), 7.17-7.11 (m, 1H), 7.10-7.03 (m, 1H),5.24 (br. s., 1H), 3.98-3.79 (m, 4H), 3.50-3.35 (m, 1H), 3.27 (t, J=7.7Hz, 2H), 3.01 (br. s., 3H), 2.68 (br. s., 1H), 2.49-2.33 (m, 1H), 2.27(br. s., 1H).

Intermediate 81: (S)-6-((1-Methylpyrrolidin-3-yl)oxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting (R)-1-methylpyrrolidin-3-ol for pyridin-3-ylmethanolafforded Intermediate 81. MS(ESI) m/z: 219.1 (M+H)⁺.

Intermediate 82: 2-(Indolin-6-yloxy)-N,N-dimethylethanamine, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting 2-(dimethylamino)ethanol for pyridin-3-ylmethanol affordedIntermediate 82. MS(ESI) m/z: 207.2 (M+H)⁺.

Intermediate 83: 6-((1-Methylpiperidin-4-yl)oxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 75,substituting 1-methylpiperidin-4-ol for pyridin-3-ylmethanol affordedIntermediate 83. MS(ESI) m/z: 233.2 (M+H)⁺.

Intermediate 84: Methyl 2-(indolin-6-yloxy)acetate

According to the procedure for the preparation of Intermediate 69,substituting methyl 2-bromoacetate for 2-iodopropane affordedIntermediate 84. MS(ESI) m/z: 208.1 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 7.38 (d, J=8.5 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 7.02 (dd,J=8.4, 2.3 Hz, 1H), 4.77 (s, 2H), 3.86 (t, J=7.7 Hz, 2H), 3.78-3.75 (m,3H), 3.24 (t, J=7.7 Hz, 2H).

Intermediate 85: 6-(Oxetan-3-ylmethoxy)indoline, TFA

According to the procedure for the preparation of Intermediate 75,substituting 3-(bromomethyl)oxetane for pyridin-3-ylmethanol affordedIntermediate 85. MS(ESI) m/z: 206.1 (M+H)⁺.

Intermediate 86: 6-(2-(Pyrrolidin-1-yl)ethoxy)indoline, 2TFA

According to the procedure for the preparation of Intermediate 69,substituting methyl 1-(2-bromoethyl)pyrrolidine, hydrobromide for2-iodopropane afforded Intermediate 86. MS(ESI) m/z: 233.1 (M+H)⁺.

Intermediate 87:1-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanone

Intermediate 87A:2-(4-Bromophenyl)-1-(6-(2-hydroxy-2-methylpropoxy)indolin-1-yl)ethanone

To a mixture of 2-(4-bromophenyl)acetic acid (92 mg, 0.43 mmol),Intermediate 74 (138 mg, 0.43 mmol), and HATU (245 mg, 0.644 mmol) inDMF (5 mL), was add DIEA (0.375 mL, 2.15 mmol). The mixture was stirredrt for 16 h. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-80% EtOAc/Hex) to affordIntermediate 87A (162 mg, 93% yield) as a colorless foam. MS(ESI) m/z:404.0 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ 7.93 (d, J=2.2 Hz, 1H),7.49-7.44 (m, 2H), 7.20-7.14 (m, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 1H),6.60 (dd, J=8.3, 2.2 Hz, 1H), 4.11-4.02 (m, 2H), 3.77 (s, 2H), 3.72 (s,2H), 3.10 (t, J=8.4 Hz, 2H), 1.36-1.28 (m, 6H).

Intermediate 87

To a mixture of Intermediate 87A (163 mg, 0.403 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (123 mg,0.484 mmol), and potassium acetate (119 mg, 1.21 mmol) in dioxane (4mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (8.9 mg, 0.012 mmol). Thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 2 h. The reaction mixture was diluted with water,then was extracted with EtOAc. The organic phase was concentrated andthe residue was purified by flash chromatography (0-80% EtOAc/Hex) toafford Intermediate 87 (178 mg, 98% yield). MS(ESI) m/z: 452.2 (M+H)⁺;¹H NMR (500 MHz, chloroform-d) δ 7.95 (d, J=2.2 Hz, 1H), 7.81-7.77 (m,J=8.3 Hz, 2H), 7.34-7.30 (m, J=8.0 Hz, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.59(dd, J=8.1, 2.3 Hz, 1H), 4.05 (t, J=8.4 Hz, 2H), 3.80 (d, J=13.2 Hz,4H), 3.07 (t, J=8.3 Hz, 2H), 1.34 (s, 12H), 1.24-1.22 (m, 6H).

Intermediate 88: N,N-Dimethylindoline-6-carboxamide, TFA

Intermediate 88A: N,N-Dimethyl-1H-indole-6-carboxamide

To a mixture of 1H-indole-6-carboxylic acid (110 mg, 0.683 mmol),dimethylamine, HCl (83 mg, 1.024 mmol), and HATU (389 mg, 1.024 mmol) inDMF (3 mL), was added DIEA (0.596 mL, 3.41 mmol). The mixture wasstirred rt for 2 h, then was concentrated. The mixture was purified byprep HPLC to afford Intermediate 88A (125 mg, 97% yield). MS(ESI) m/z:189.0 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ 9.56 (br. s., 1H), 7.61(d, J=8.0 Hz, 1H), 7.38-7.34 (m, 1H), 7.24-7.19 (m, 1H), 7.12 (dd,J=8.1, 1.5 Hz, 1H), 6.53-6.48 (m, 1H), 3.27-3.05 (m, 3H), 2.99 (br. s.,3H).

Intermediate 88

To a solution of Intermediate 88A (125 mg, 0.664 mmol) in AcOH (3 mL) at0° C. was added Sodium cyanoborohydride (83 mg, 1.328 mmol). The mixturewas stirred at 0° C. for 5 min, warmed to rt and stirred for 5 h. Thereaction mixture was made basic with 20% NaOH at 0° C., then wasextracted with DCM (3×70 mL). The organic layer was washed with brine,dried over Na₂SO₄, concentrated and purified via preparative HPLC toafford Intermediate 88 (155 mg, 0.509 mmol, 77% yield) as a yellow oil.MS(ESI) m/z: 191.1 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.60-7.53 (m,1H), 7.52-7.46 (m, 2H), 3.89 (t, J=7.8 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H),3.11 (s, 3H), 3.00 (s, 3H).

Intermediate 89: Indolin-6-yl(4-methylpiperazin-1-yl)methanone, 2TFA

According to the procedure for the preparation of Intermediate 88,substituting 1-methylpiperazine for dimethylamine, HCl affordedIntermediate 89. MS(ESI) m/z: 246.1 (M+H)⁺.

Intermediate 90: (4-Hydroxypiperidin-1-yl)(indolin-5-yl)methanone

According to the procedure for the preparation of Intermediate 88,substituting piperidin-4-ol for dimethylamine, HCl and1H-indole-5-carboxylic acid for 1H-indole-6-carboxylic acid affordedIntermediate 90. MS(ESI) m/z: 247.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 7.16-7.12 (m, 1H), 7.03 (dd, J=8.0, 1.7 Hz, 1H), 6.51(d, J=7.9 Hz, 1H), 3.93 (br. s., 1H), 3.84 (tt, J=8.3, 4.0 Hz, 2H),3.64-3.41 (m, 4H), 3.19 (ddd, J=13.2, 9.5, 3.3 Hz, 2H), 2.99 (t, J=8.5Hz, 2H), 1.88-1.73 (m, 2H), 1.57-1.41 (m, 2H).

Intermediate 91: (4-Hydroxypiperidin-1-yl)(indolin-6-yl)methanone, TFA

According to the procedure for the preparation of Intermediate 88,substituting piperidin-4-ol for dimethylamine, HCl afforded Intermediate91. MS(ESI) m/z: 247.1 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄) δ 7.57 (dd,J=7.7, 0.8 Hz, 1H), 7.51-7.47 (m, 2H), 4.16 (br. s., 1H), 3.95-3.88 (m,3H), 3.60 (br. s., 1H), 3.37 (t, J=7.8 Hz, 3H), 3.28-3.17 (m, 1H),2.02-1.88 (m, 1H), 1.82 (br. s., 1H), 1.57 (br. s., 1H), 1.46 (br. s.,1H).

Intermediate 92: Indolin-6-yl(morpholino)methanone, TFA

According to the procedure for the preparation of Intermediate 88,substituting morpholine for dimethylamine, HCl afforded Intermediate 92.MS(ESI) m/z: 233.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 12.19 (br.s., 3H), 7.42 (d, J=7.9 Hz, 1H), 7.35 (dd, J=7.8, 1.2 Hz, 1H), 7.20 (s,1H), 3.93 (t, J=7.8 Hz, 2H), 3.77 (br. s., 4H), 3.60 (br. s., 2H),3.42-3.24 (m, 4H).

Intermediate 93: Indolin-5-yl(morpholino)methanone

According to the procedure for the preparation of Intermediate 88,substituting morpholine for dimethylamine, HCl and1H-indole-5-carboxylic acid for 1H-indole-6-carboxylic acid affordedIntermediate 93. MS(ESI) m/z: 233.1 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 7.19 (d, J=1.1 Hz, 1H), 7.11-7.06 (m, 1H), 6.53 (d,J=8.1 Hz, 1H), 4.04 (br. s., 1H), 3.76-3.54 (m, 10H), 3.02 (t, J=8.6 Hz,2H).

Intermediate 94: 4-(4-Amino-2-methylphenyl)phthalazin-1(2H)-one, TFA

Intermediate 94A: tert-Butyl (4-bromo-3-methylphenyl)carbamate

To a solution of 4-bromo-3-methylaniline (2.0 g, 10.8 mmol) and Boc₂O(2.82 g, 12.9 mmol) in MeOH (20 mL), was added sodium carbonate (2.51 g,23.7 mmol). The mixture was stirred at rt for 5 h. Additional Boc₂O(0.28 g, 1.3 mmol) was added and the mixture was stirred at rt for 20 h.The reaction mixture was filtered to remove inorganic salt. The filtratewas concentrated to give a white solid, which was suspended in EtOAc(˜100 mL). The suspension was filtered through a 1″ pad of SiO₂. Thefiltrate was concentrated to afford Intermediate 94A (3.03 g, 98% yield)as a white solid. MS(ESI) m/z: 307.9 (M+Na)⁺; ¹H NMR (400 MHz,chloroform-d) δ 7.40 (d, J=8.6 Hz, 1H), 7.32 (d, J=1.8 Hz, 1H), 7.02(dd, J=8.6, 2.6 Hz, 1H), 6.38 (br. s., 1H), 2.36 (s, 3H), 1.51 (s, 9H).

Intermediate 94B: tert-Butyl(4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-3-methylphenyl)carbamate

To a vial containing Intermediate 94A (1.5 g, 5.24 mmol),5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (1.30 g, 5.77 mmol)and potassium acetate (1.54 g, 15.7 mmol), was added dioxane (15 ml).The mixture was degassed (evacuated and flushed with Ar (3×)), thenPdCl₂(dppf) CH₂Cl₂ adduct (0.214 g, 0.262 mmol) was added. The mixturewas degassed (3×), then the vial was sealed and heated at 110° C. for2.5 h. The reaction mixture was partitioned between EtOAc and H₂O. Theorganic phase was washed with H₂O and brine, dried (Na₂SO₄), filteredthrough a 1″ pad of SiO₂ and concentrated. The crude product waspurified by flash chromatography (gradient from 0 to 50% ethylacetate/hexanes) to afford Intermediate 94B (1.545 g, 4.84 mmol, 92%yield) as an orange foam. MS(ESI) m/z: 250.2 (M(boronic acid)-H)⁻; ¹HNMR (400 MHz, chloroform-d) δ 7.67 (d, J=8.1 Hz, 1H), 7.17 (s, 1H), 7.11(dd, J=8.1, 2.0 Hz, 1H), 6.41 (br. s., 1H), 3.75 (s, 4H), 2.49 (s, 3H),1.51 (s, 9H), 1.02 (s, 6H).

Intermediate 94C: tert-Butyl(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To 4-chlorophthalazin-1(2H)-one (400 mg, 2.22 mmol), Intermediate 94B(778 mg, 2.44 mmol) and phosphoric acid, potassium salt (1175 mg, 5.54mmol), were added dioxane (6 mL) and water (0.667 mL). The mixture wasdegassed (evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (128 mg, 0.111mmol) was added, then the mixture was degassed (2×). The reaction vialwas sealed and heated in a microwave reactor at 150° C. for 40 min. Thereaction mixture was partitioned between EtOAc and H₂O. The organicphase was washed with H₂O and brine, dried (Na₂SO₄) and concentrated.The crude product was purified by flash chromatography (gradient from 0to 100% ethyl acetate/hexanes) to afford Intermediate 94C (540 mg, 1.54mmol, 69% yield) as a white solid. MS(ESI) m/z: 352.0 (M+H)⁺; ¹H NMR(400 MHz, methanol-d₄) δ 8.46-8.40 (m, 1H), 7.91-7.80 (m, 2H), 7.47-7.35(m, 3H), 7.20 (d, J=8.1 Hz, 1H), 2.09 (s, 3H), 1.54 (s, 9H).

Intermediate 94

To a suspension of Intermediate 94C (540 mg, 1.54 mmol) in DCM (5 mL),was added TFA (2 mL). The mixture was stirred at rt for 2 h. Thereaction mixture was concentrated, then was co-evaporated with DCM (3×)to afford Intermediate 94 (723 mg, 98% yield) as a solid. MS(ESI) m/z:252.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.45 (dd, J=7.9, 1.1 Hz,1H), 7.93-7.82 (m, 2H), 7.48 (d, J=8.1 Hz, 1H), 7.38-7.27 (m, 3H), 2.19(s, 3H)

Intermediate 95: 4-(Dimethylamino)-N-(indolin-6-yl)benzamide, 2TFA

Intermediate 95A: tert-Butyl 6-nitroindoline-1-carboxylate

To a mixture of 6-nitroindoline (300 mg, 1.83 mmol) and Boc₂O (0.509 mL,2.19 mmol) in THF at rt, was added cat. DMAP. The resulting mixture wasstirred rt o/n. The reaction mixture was concentrated and the residuewas purified by flash chromatography (0-20% EtOAc/Hex) to affordIntermediate 95A (480 mg, 99% yield). MS(ESI) m/z: 287.0 (M+Na)⁺; ¹H NMR(500 MHz, methanol-d₄) δ 8.51 (br. s., 1H), 7.81 (dd, J=8.3, 2.2 Hz,1H), 7.33 (d, J=8.3 Hz, 1H), 4.12-4.02 (m, 2H), 3.25-3.16 (m, 2H),1.67-1.49 (m, 9H).

Intermediate 95B: tert-Butyl 6-Aminoindoline-1-carboxylate

To a degassed mixture of Intermediate 95A (450 mg, 1.70 mmol) in MeOH(10 mL), was add 10% Pd/C. The mixture was stirred rt for 2 h under H2(balloon). The reaction mixture was filtered and concentrated. Theresidue was purified by flash chromatography (0-40% EtOAc/Hex) to affordIntermediate 95B (300 mg, 75% yield). MS(ESI) m/z: 235.1 (M+H)⁺; ¹H NMR(500 MHz, chloroform-d) δ 7.78-7.14 (m, 1H), 6.54-6.42 (m, 2H), 3.90(br. s., 2H), 3.61-3.40 (m, 2H), 2.96 (t, J=8.5 Hz, 2H), 1.71-1.46 (m,9H).

Intermediate 95C: tert-Butyl6-(4-(dimethylamino)benzamido)indoline-1-carboxylate

To a mixture of 4-(dimethylamino)benzoyl chloride (22 mg, 0.12 mmol) andIntermediate 95B (23 mg, 0.098 mmol) in DCM (2 mL) at 0° C., was addedDIEA (0.051 mL, 0.30 mmol). The mixture was stirred rt for 1 h, then wasconcentrated. The residue was purified by flash chromatography (0-60%EtOAc/Hex) to afford Intermediate 95C (17 mg, 45.4% yield). MS(ESI) m/z:382.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.17-8.02 (m, 1H),7.91-7.82 (m, 2H), 7.60 (br. s., 1H), 7.15 (d, J=8.6 Hz, 2H), 4.07-3.97(m, 2H), 3.19-3.14 (m, 6H), 3.12-3.05 (m, 2H), 1.58 (br. s., 9H)

Intermediate 95

Intermediate 95C (17 mg, 0.045 mmol) stirred with TFA and DCM for 20min, then was concentrated to afford Intermediate 95 (19 mg). MS(ESI)m/z: 282.1 (M+H)⁺: ¹H NMR (400 MHz, methanol-d₄) δ 7.94-7.85 (m, 3H),7.76-7.67 (m, 1H), 7.44 (d, J=8.6 Hz, 1H), 6.90-6.81 (m, 2H), 3.93-3.87(m, 2H), 3.35 (t, J=7.7 Hz, 2H), 3.07 (s, 6H).

Intermediate 96: 4-(4-Amino-2-chlorophenyl)phthalazin-1 (2H)-one

Intermediate 96A: tert-Butyl (4-bromo-3-chlorophenyl)carbamate

To a solution of 4-bromo-3-chloroaniline (1.5 g, 7.3 mmol) and Boc₂O(2.38 g, 10.9 mmol) in MeOH (20 mL), was added sodium carbonate (1.694g, 15.98 mmol). The mixture was stirred at rt for 16 h. The reactionmixture was concentrated. The residue was suspended in water, thenextracted with DCM. The organic phase was concentrated and the residuewas purified by flash chromatography (0-20% EtOAc/Hex) to affordIntermediate 96A (2.0 g, 6.52 mmol, 90% yield). ¹H NMR (400 MHz,chloroform-d) δ 7.64 (d, J=2.4 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.08(dd, J=8.7, 2.5 Hz, 1H), 6.46 (br. s., 1H), 1.53-1.51 (m, 9H).

Intermediate 96B: tert-Butyl(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

A mixture of Intermediate 96A (1.96 g, 6.39 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.79 g,7.03 mmol), and potassium acetate (1.88 g, 19.2 mmol) in dioxane (10mL). Then PdCl₂(dppf) CH₂Cl₂ adduct (0.14 g, 0.19 mmol) was added, thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 16 h. The reaction was quenched with water,extracted with EtOAc, concentrated and purified through via flashchromatography (0-40% EtOAc/Hex) to Intermediate 96B (1.40 g, 62%yield). MS(ESI) m/z: 298.1 (M-(t-Bu)+2H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 7.63 (d, J=8.1 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.18(dd, J=8.1, 2.0 Hz, 1H), 6.50 (s, 1H), 1.52 (s, 9H), 1.40-1.33 (m, 12H).

Intermediate 96C: tert-Butyl(3-chloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To 4-chlorophthalazin-1(2H)-one (100 mg, 0.554 mmol), Intermediate 96B(206 mg, 0.581 mmol) and phosphoric acid, potassium salt (294 mg, 1.38mmol), were added dioxane (5 mL) and water (0.556 mL). The mixture wasdegassed (evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (32 mg, 0.028mmol) was added, then the mixture was degassed (2×). The reaction vialwas sealed and heated in a microwave reactor at 150° C. for 30 min. Thereaction mixture was concentrated, then purified by flash chromatography(0-80% EtOAc/Hex) to afford Intermediate 96C (200 mg, 97% yield). (ESI)m/z: 372.0 (M+H)⁺.

Intermediate 96

Intermediate 96C (200 mg, 0.538 mmol) was stirred with TFA (2 mL) andDCM (3 ml) at rt for 30 min. The reaction mixture was concentrated andthe residue was purified by flash chromatography (0-100% EtOAc/Hex) toafford Intermediate 96 (120 mg, 82% yield). MS(ESI) m/z 272.0 (M+H)⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.36-8.22 (m, 1H), 7.93-7.78 (m,2H), 7.41-7.24 (m, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H),6.64 (dd, J=8.4, 2.2 Hz, 1H), 5.75 (s, 1H).

Intermediate 97:N-(3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)indoline-1-carboxamide

Intermediate 97A: N-(4-Bromo-3-methylphenyl)indoline-1-carboxamide

To a solution of 1-bromo-4-isocyanato-2-methylbenzene (111 mg, 0.523mmol) in CH₂Cl₂ (1 mL), was added indoline (68.6 mg, 0.576 mmol) inCH₂Cl₂ (1 mL). The mixture was stirred at rt for 1 h, then wasconcentrated. The residue was purified by flash chromatography (0-50%EtOAc/Hex) to afford Intermediate 97A (170 mg, 0.513 mmol, 98% yield) asa white solid. MS(ESI) m/z: 331.0 (M+H)⁺.

Intermediate 97

A mixture of Intermediate 97A (170 mg, 0.513 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (143 mg,0.565 mmol), and potassium acetate (151 mg, 1.54 mmol) in dioxane (10mL). PdCl₂(dppf) CH₂Cl₂ adduct (11.27 mg, 0.015 mmol) was added, thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 3 h. The reaction was quenched with water andextracted with EtOAc. The organic phase was concentrated and the residuewas purified via flash chromatography (0-40% EtOAc/Hex) to affordIntermediate 97 (100 mg, 0.264 mmol, 51.5% yield). MS(ESI) m/z: 379.1(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.89 (d, J=7.9 Hz, 1H), 7.74(d, J=8.1 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.26-7.16 (m, 3H), 7.01-6.93(m, 1H), 6.50 (s, 1H), 4.08 (t, J=8.5 Hz, 2H), 3.23 (t, J=8.6 Hz, 2H),2.54 (s, 3H), 1.35 (s, 12H).

Intermediate 98: Methyl2-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1H-indazol-1-yl)acetate

Intermediate 98A: tert-Butyl3-((4-bromophenyl)carbamoyl)-1H-indazole-1-carboxylate

To a solution of 4-bromoaniline (63.0 mg, 0.366 mmol),1-(I-butoxycarbonyl)-1H-indazole-3-carboxylic acid (96 mg, 0.366 mmol),and HATU (146 mg, 0.384 mmol) in DMF (3 mL), was added DIEA (0.32 mL,1.83 mmol). The reaction mixture was stirred at rt for 16 h, then wasdiluted with water. The mixture was extracted with EtOAc. The organicphase was washed with 10% LiCl and brine, then concentrated. The residuewas purified by flash chromatography (0-20% EtOAc/Hex) to affordIntermediate 98A (118 mg, 77% yield). MS(ESI) m/z: 416.1 (M+H)⁺; ¹H NMR(400 MHz, chloroform-d) δ 8.98 (s, 1H), 8.48 (dt, J=8.0, 0.9 Hz, 1H),8.12 (d, J=8.6 Hz, 1H), 7.72-7.65 (m, 2H), 7.63-7.56 (m, 1H), 7.54-7.48(m, 2H), 7.45 (ddd, J=8.1, 7.1, 0.9 Hz, 1H), 1.78 (s, 9H).

Intermediate 98B: N-(4-Bromophenyl)-1H-indazole-3-carboxamide

Intermediate 98A (118 mg, 0.283 mmol) was stirred with TFA (1 mL) andDCM (2 mL) for 30 min at rt, then was concentrated. The residue waspurified by flash chromatography (0-50% EtOAc/Hex) to affordIntermediate 98B (65 mg, 0.206 mmol, 72.5% yield) as a yellow solid.MS(ESI) m/z: 316.0 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.80 (br. s.,1H), 10.49 (s, 1H), 8.22 (d, J=8.1 Hz, 1H), 7.99-7.84 (m, 2H), 7.67 (d,J=8.4 Hz, 1H), 7.57-7.49 (m, 2H), 7.46 (ddd, J=8.3, 7.0, 1.0 Hz, 1H),7.34-7.24 (m, 1H).

Intermediate 98C: Methyl2-(3-((4-bromophenyl)carbamoyl)-1H-indazol-1-yl)acetate

To a vial containing Intermediate 98B (65 mg, 0.21 mmol) in DMF (3 mL),were added methyl 2-bromoacetate (38 mg, 0.25 mmol) and K₂CO₃ (43 mg,0.31 mmol). The vial was sealed and the mixture was stirred at rt for 3h. The reaction mixture was concentrated, then the residue was dilutedwith water and extracted with EtOAc. The organic phase was dried overNa₂SO₄ and concentrated. The residue was purified by flashchromatography (0-50% EtOAc/Hex) to afford Intermediate 98C (70 mg, 88%yield) as a yellow solid. MS(ESI) m/z: 388.0 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.80 (s, 1H), 8.44 (dt, J=8.1, 1.0 Hz, 1H), 7.70-7.60(m, 2H), 7.55-7.45 (m, 3H), 7.41-7.32 (m, 2H), 5.20 (s, 2H), 3.79 (s,3H).

Intermediate 98

To a mixture of Intermediate 98C (72 mg, 0.19 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (51.8 mg,0.204 mmol), and potassium acetate (54.6 mg, 0.556 mmol) in dioxane (10mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (4.1 mg, 5.6 μmol). Thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 3 h. The reaction was diluted with water, then wasextracted with EtOAc. The organic phase was concentrated, then theproduct was purified by flash chromatography (0-50% EtOAc/Hex) to affordIntermediate 98 (80 mg, 99% yield) as a colorless oil. MS(ESI) m/z:388.0 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.89 (s, 1H), 8.46 (dt,J=8.1, 1.0 Hz, 1H), 7.89-7.82 (m, 2H), 7.81-7.73 (m, 2H), 7.53-7.43 (m,1H), 7.35 (td, J=8.1, 1.0 Hz, 2H), 5.21 (s, 2H), 3.78 (s, 3H), 1.36 (s,12H).

Intermediate 99: Methyl3-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1H-indazol-1-yl)propanoate

According to the procedure for the preparation of Intermediate 98,substituting methyl 3-bromopropanoate for methyl 2-bromoacetate affordedIntermediate 99. MS(ESI) m/z: 450.3 (M+H)⁺.

Intermediate 100:1-(3-Hydroxy-3-methylbutyl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-indazole-3-carboxamide

Intermediate 100A: Methyl3-(3-((4-bromophenyl)carbamoyl)-1H-indazol-1-yl)propanoate

To a vial containing Intermediate 98B (150 mg, 0.474 mmol) in DMF (3mL), were added methyl 3-bromopropanoate (95 mg, 0.569 mmol) and K₂CO₃(98 mg, 0.712 mmol). The vial was sealed and the mixture was stirred atrt for 3 h. The reaction mixture was concentrated, and the residue wasdiluted with water and extracted with EtOAc. The organic phase was driedover Na₂SO₄ and concentrated. The residue was purified by flashchromatography (0-50% EtOAc/Hex) to afford Intermediate 100A (180 mg,94% yield). MS(ESI) m/z: 402.2 (M+H)⁺; ¹H NMR (500 MHz, chloroform-d) δ8.80 (s, 1H), 8.39 (d, J=8.3 Hz, 1H), 7.68-7.63 (m, 2H), 7.56-7.44 (m,4H), 7.32 (ddd, J=8.0, 6.9, 0.8 Hz, 1H), 4.71 (t, J=6.9 Hz, 2H),3.73-3.66 (m, 3H), 3.05 (t, J=6.7 Hz, 2H).

Intermediate 100B:N-(4-Bromophenyl)-1-(3-hydroxy-3-methylbutyl)-1H-indazole-3-carboxamide

Intermediate 100A (85 mg, 0.211 mmol) was treated with 3Mmethylmagnesium chloride (0.704 mL, 2.11 mmol) at 0° C. to affordIntermediate 100B (68 mg, 80% yield) as a colorless oil. MS(ESI) m/z:402.1 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.84 (s, 1H), 8.40 (dt,J=8.2, 1.0 Hz, 1H), 7.71-7.63 (m, 2H), 7.52-7.40 (m, 4H), 7.31 (ddd,J=8.1, 6.7, 1.1 Hz, 1H), 4.64-4.52 (m, 2H), 2.20-2.09 (m, 2H), 1.34 (s,6H).

Intermediate 100

A mixture of Intermediate 100B (70 mg, 0.17 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (49 mg,0.191 mmol), and potassium acetate (51 mg, 0.52 mmol) in dioxane (10mL). Then PdCl₂(dppf) CH₂Cl₂ adduct (3.8 mg, 5.22 mol) was added, thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 3 h. The reaction progress was quenched withwater, extracted with EtOAc. The organic phase was concentrated and waspurified by flash chromatography (0-50% EtOAc/Hex) to affordIntermediate 100 (78 mg, 100% yield). MS(ESI) m/z: 450.3.

Intermediate 101:1-((1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl)-1H-indazole-3-carboxylicacid

According to the procedure for the preparation of Intermediate 21,substituting tert-butyl 4-(bromomethyl)piperidine-1-carboxylate,hydrobromide for benzyl 4-(bromomethyl)piperidine-1-carboxylate affordedIntermediate 101. MS(ESI) m/z: 360.3 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 8.14 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.47-7.40(m, 1H), 7.31-7.25 (m, 1H), 4.36 (d, J=7.2 Hz, 2H), 4.06-3.97 (m, 2H),2.66 (br. s., 2H), 2.21 (ddt, J=11.2, 7.5, 3.8 Hz, 1H), 1.53-1.45 (m,2H), 1.44-1.35 (m, 9H), 1.26-1.17 (m, 2H).

Intermediate 102: 4-(4-Amino-2-methoxyphenyl)phthalazin-1(2H)-one, TFA

Intermediate 102A: tert-Butyl (4-bromo-3-methoxyphenyl)carbamate

To a solution of 4-bromo-3-methoxyaniline, HCl (0.6 g, 2.5 mmol) andBoc₂O (0.824 g, 3.77 mmol) in MeOH (10 mL), was added sodium carbonate(0.80 g, 7.55 mmol). The mixture was stirred at rt for 3 h. The reactionmixture was concentrated and the residue was purified by flashchromatography (0-20% EtOAc/Hex) to afford Intermediate 102A (550 mg,72% yield). MS(ESI) m/z: 302.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ7.39 (d, J=8.4 Hz, 1H), 7.32 (s, 1H), 6.63 (dd, J=8.5, 2.3 Hz, 1H), 6.49(br. s., 1H), 3.91 (s, 3H), 1.55-1.48 (m, 9H).

Intermediate 102B: tert-Butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate

To a mixture of Intermediate 102A (340 mg, 1.13 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (314 mg,1.24 mmol), and potassium acetate (331 mg, 3.38 mmol) in dioxane (8 mL),was added PdCl₂(dppf) CH₂Cl₂ adduct (24.7 mg, 0.034 mmol). The reactionmixture was degassed (3× vacuum/Ar), sealed in a vial and heated at 110°C. for 3 h. The reaction was diluted with water and extracted withEtOAc. The organic phase was concentrated and the residue was purifiedby flash chromatography (0-50% EtOAc/Hex) to afford Intermediate 102B(200 mg, 51% yield) as a colorless foam. MS(ESI) m/z: 350.3 (M+H)⁺; ¹HNMR (500 MHz, chloroform-d) δ 7.59 (d, J=8.0 Hz, 1H), 7.18 (br. s., 1H),6.81 (br. s., 1H), 6.75 (dd, J=8.1, 1.8 Hz, 1H), 3.81 (s, 3H), 1.54-1.48(m, 9H), 1.36-1.31 (m, 12H).

Intermediate 102C: tert-Butyl(3-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To a 5 mL of microwave vial containing solution of Intermediate 102B(155 mg, 0.443 mmol) in dioxane (3 mL) were added potassium phosphatetribasic (235 mg, 1.107 mmol), dioxane (3 mL), water (0.3 mL) andPdCl₂(dppf) CH₂Cl₂ adduct (36.2 mg, 0.044 mmol) at RT. The reaction waspurged with nitrogen and then was heated with microwave at 130° C. for15 min. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-80% EtOAc/Hex) to affordIntermediate 102C (88 mg, 54% yield). MS(ESI) m/z: 368.2 (M+H)⁺; ¹H NMR(400 MHz, chloroform-d) δ 9.83 (s, 1H), 8.47 (dd, J=7.6, 1.2 Hz, 1H),7.84-7.63 (m, 2H), 7.48 (s, 1H), 7.45-7.34 (m, 1H), 6.84 (dd, J=8.1, 2.0Hz, 1H), 6.64 (s, 1H), 3.76 (s, 3H), 1.57 (s, 9H).

Intermediate 102

Intermediate 102C (85 mg, 0.231 mmol) was stirred with TFA (1 ml) andDCM (2 ml) at rt for 30 min, concentrated to give Intermediate 102 (78mg, 88% yield). MS(ESI) m/z: 268.2 (M+H)⁺; ¹H NMR (500 MHz, methanol-d₄)δ 8.42-8.37 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.50 (d, J=8.0 Hz,1H), 7.37-7.33 (m, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.14 (dd, J=8.0, 1.9 Hz,1H), 3.82-3.76 (m, 3H).

Intermediate 103: 4-(4-Amino-2-ethoxyphenyl)phthalazin-1 (2H)-one

According to the procedure for the preparation of Intermediate 102,substituting 4-bromo-3-ethoxyaniline for 4-bromo-3-methoxyaniline, HClafforded after flash chromatography (0-90% EtOAc/Hex) Intermediate 103.MS(ESI) m/z: 282.2 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (s, 1H),8.33-8.13 (m, 1H), 7.90-7.72 (m, 2H), 7.44-7.33 (m, 1H), 6.95 (d, J=8.1Hz, 1H), 6.34 (d, J=1.8 Hz, 1H), 6.26 (dd, J=7.9, 2.0 Hz, 1H), 5.38 (s,2H), 3.97-3.81 (m, 2H), 0.97 (t, J=7.0 Hz, 3H).

Intermediate 104: 4-(4-Amino-3-methoxyphenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Intermediate 102,substituting 4-bromo-2-methoxyaniline, HCl for 4-bromo-3-methoxyaniline,HCl afforded after flash chromatography (0-100% EtOAc/Hex) Intermediate104. MS(ESI) m/z: 268.2 (M+H)⁺; ¹H NMR (400 MHz, THF) δ 11.64 (br. s.,1H), 8.43-8.34 (m, 1H), 7.87-7.81 (m, 1H), 7.77-7.69 (m, 2H), 7.01 (d,J=1.8 Hz, 1H), 6.91 (dd, J=7.9, 2.0 Hz, 1H), 6.71 (d, J=7.9 Hz, 1H),3.84 (s, 3H).

Intermediate 105: 4-(4-Amino-3-hydroxyphenyl)phthalazin-1(2H)-one

Intermediate 105A: tert-Butyl(2-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

According to the procedure for the preparation of Intermediate 102C,substituting 4-bromo-2-methoxyaniline, HCl for 4-bromo-3-methoxyaniline,HCl afforded Intermediate 105A.

Intermediate 105

To a solution of Intermediate 105A (25 mg, 0.068 mmol) in DCM (2 mL),was add boron tribromide (0.34 mL, 0.34 mmol). The mixture was stirredat rt o/n, then was diluted with water and made basic with Na₂CO₃. Themixture was extracted with EtOAc, then the organic phase wasconcentrated. The residue was purified by flash chromatography (0-100%EtOAc/Hex) to afford Intermediate 105 (8 mg, 46% yield). MS(ESI) m/z:254.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 7.21-7.15 (m, 1H),6.72-6.65 (m, 1H), 6.64-6.57 (m, 2H), 5.72 (d, J=1.8 Hz, 1H), 5.70-5.58(m, 2H).

Intermediate 106: Methyl5-amino-2-(4-oxo-3,4-dihydrophthalazin-1-yl)benzoate

Intermediate 106A: Methyl 2-bromo-5-((tert-butoxycarbonyl)amino)benzoate

To a solution of methyl 5-amino-2-bromobenzoate (0.45 g, 1.96 mmol) andBoc₂O (0.64 g, 2.93 mmol) in MeOH (10 mL), was added sodium carbonate(0.456 g, 4.30 mmol). The mixture was stirred at rt for 16 h, then wasconcentrated. The residue was diluted with water and extracted with DCM.The organic phase was concentrated and the residue was purified by flashchromatography (0-20% EtOAc/Hex) to afford Intermediate 106A (540 mg,84% yield). MS(ESI) m/z: 330.1 (M+H)⁺.

Intermediate 106B: Methyl5-((tert-butoxycarbonyl)amino)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

To a mixture of Intermediate 106A (360 mg, 1.09 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (305 mg,1.20 mmol), and potassium acetate (321 mg, 3.27 mmol) in dioxane (3 mL),was added PdCl₂(dppf) CH₂Cl₂ adduct (24 mg, 0.033 mmol). The reactionmixture was degassed (3× vacuum/Ar), sealed in a vial and heated at 110°C. for 3 h. The reaction mixture was diluted with water, then extractedwith EtOAc. The organic phase was concentrated and the residue waspurified by flash chromatography (0-40% EtOAc/Hex) to affordIntermediate 106B (310 mg, 75% yield) as a yellow oil. MS(ESI) m/z:376.3 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ ppm 7.95 (1H, d, J=1.98Hz), 7.54 (1H, dd, J=8.14, 1.76 Hz), 7.40 (1H, d, J=7.92 Hz), 7.03 (1H,s), 3.87 (3H, s), 1.50 (9H, s), 1.39 (12H, s).

Intermediate 106C: Methyl5-((tert-butoxycarbonyl)amino)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)benzoate

To a 5 mL of microwave vial containing a solution of Intermediate 106B(92 mg, 0.24 mmol) in dioxane (3 mL) were added4-chlorophthalazin-1(2H)-one (40 mg, 0.22 mmol), potassium phosphatetribasic (118 mg, 0.554 mmol), water (0.3 mL) and PdCl₂(dppf) CH₂Cl₂adduct (18.09 mg, 0.022 mmol) at RT. The reaction was purged withnitrogen, sealed and then heated in a microwave reactor at 130° C. for15 min. The reaction mixture was diluted with water, then was extractedwith EtOAc. The organic phase was concentrated and the residue waspurified by flash chromatography (0-80% EtOAc/Hex) to affordIntermediate 106C (38 mg, 43% yield) as a white solid. MS(ESI) m/z:396.3 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.44-8.38 (m, 1H), 8.22(d, J=2.4 Hz, 1H), 7.88-7.76 (m, 3H), 7.42 (d, J=8.4 Hz, 1H), 7.37-7.31(m, 1H), 3.55 (s, 3H), 1.56 (s, 9H).

Intermediate 106

Intermediate 106C (66 mg, 0.17 mmol) was stirred with TFA (1 mL) and DCM(1 mL) at rt for 30 min, then was concentrated. The residue was purifiedby flash chromatography (0-90% EtOAc/Hex) to afford Intermediate 106 (47mg, 95% yield). MS(ESI) m/z: 296.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄)δ 8.48-8.36 (m, 1H), 7.87-7.75 (m, 2H), 7.46-7.38 (m, 1H), 7.36 (d,J=2.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.96 (dd, J=8.1, 2.4 Hz, 1H),3.49 (s, 3H).

Intermediate 107: 4-(4-Amino-3-fluorophenyl)phthalazin-1(2H)-one, TFA

Intermediate 107A: tert-Butyl(2-fluoro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

To a vial containing 4-chlorophthalazin-1(2H)-one (100 mg, 0.554 mmol),(4-((tert-butoxycarbonyl)amino)-3-fluorophenyl)boronic acid (155 mg,0.609 mmol) and potassium phosphate tribasic (294 mg, 1.38 mmol), wereadded dioxane (1.8 mL) and water (0.2 mL). The mixture was degassed(evacuated and flushed with Ar (3×)), then was treated with Pd(Ph₃P)₄(32 mg, 0.028 mmol). The mixture was degassed (3×), then the vial wassealed and heated in a microwave reactor at 150° C. for 30 min. Themixture was partitioned between EtOAc and H₂O. The aqueous phase wasextracted with EtOAc. The combined organic phase was washed with brine,dried (Na₂SO₄) and concentrated. The crude product was purified by flashchromatography (gradient from 0 to 100% ethyl acetate/hexanes) to affordIntermediate 107A as a white solid (124 mg, 63% yield). MS(ESI) m/z:356.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.40-8.48 (m, 1H), 8.06(t, J=8.36 Hz, 1H), 7.86-7.96 (m, 2H), 7.81-7.86 (m, 1H), 7.35-7.43 (m,2H), 1.56 (s, 9H); ¹⁹F NMR (376 MHz, methanol-d₄) δ −129.38 (s, 1F).

Intermediate 107

To a suspension of Intermediate 107A (123 mg, 0.346 mmol) in DCM (2 mL),was added TFA (2 mL). The resultant yellow solution was stirred at rtfor 1.25 h, then was concentrated to afford Intermediate 107 (128 mg,100% yield) as a white solid. MS(ESI) m/z: 256.1 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.39-8.46 (m, 1H), 7.82-7.96 (m, 3H), 7.25 (dd,J=1.98, 11.88 Hz, 1H), 7.19 (dd, J=1.98, 8.14 Hz, 1H), 6.94-7.04 (m,1H).

Intermediate 108:4-(4-Amino-2-(hydroxymethyl)phenyl)phthalazin-1(2H)-one

To a solution of Intermediate 106C (220 mg, 0.556 mmol) in THF (1 mL)was added 2.0 M (in THF) lithium borohydride (0.684 mL, 1.37 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 16 h, then was quenched with MeOH and concentrated. The residue waspurified by flash chromatography (0-90% EtOAc/Hex) to afford tert-butyl(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate(88 mg, 59% yield). The material was stirred with TFA (1 mL) and DCM (1mL) for 30 min, then was concentrated. The residue was purified by flashchromatography (0-20% MeOH/DCM) to afford Intermediate 108 (88 mg, 59%yield). MS(ESI) m/z: 268.2 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ8.48-8.36 (m, 1H), 7.83 (quind, J=7.3, 1.5 Hz, 2H), 7.54-7.41 (m, 1H),7.23-7.15 (m, 2H), 6.93 (dd, J=7.9, 2.6 Hz, 1H), 4.42 (br. s., 2H).

Intermediate 109:1-((Tetrahydrofuran-2-yl)methyl)-1H-indazole-3-carboxylic acid

Intermediate 109A: Ethyl1-((tetrahydrofuran-2-yl)methyl)-1H-indazole-3-carboxylate

To a vial containing ethyl 1H-indazole-3-carboxylate (200 mg, 1.05 mmol)in acetonitrile (3 mL), were added 2-(bromomethyl)tetrahydrofuran (226mg, 1.37 mmol) and Cs₂CO₃ (514 mg, 1.58 mmol). The vial was sealed andthe mixture was stirred at 70° C. overnight. The reaction mixture wasdiluted with water, then was extracted with EtOAc. The organic phase waswith 10% LiCl and brine, then was concentrated. The residue was purifiedby flash chromatography (0-60% EtOAc/Hex) to afford Intermediate 109A(199 mg, 69% yield). MS(ESI) m/z: 275.2 (M+H)⁺; ¹H NMR (400 MHz,chloroform-d) δ 8.19 (dt, J=8.1, 1.0 Hz, 1H), 7.63-7.57 (m, 1H), 7.41(ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.29 (ddd, J=8.1, 7.0, 0.9 Hz, 1H),4.64-4.47 (m, 4H), 4.40 (qd, J=6.3, 4.5 Hz, 1H), 3.81-3.63 (m, 2H),2.05-1.94 (m, 1H), 1.88-1.64 (m, 3H), 1.48 (t, J=7.2 Hz, 3H).

Intermediate 109

To a solution of Intermediate 109A (205 mg, 0.747 mmol) in THF (3 mL),was added 1M lithium hydroxide (2.242 mL, 2.242 mmol), stirred at rtovernight. The reaction mixture was concentrated, then the residue wastaken up in water and EtOAc, then acidified with 1 N HCl. The phaseswere separated, then the aqueous phase was extracted with EtOAc (3×).The combined organic phase was washed with brine, dried (Na₂SO₄) andconcentrated to afford Intermediate 109 (175 mg, 95% yield) as acolorless oil. MS(ESI) m/z: 247.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄)δ 8.15 (dt, J=8.1, 1.0 Hz, 1H), 7.72 (dt, J=8.6, 0.9 Hz, 1H), 7.47 (ddd,J=8.4, 7.0, 1.1 Hz, 1H), 7.31 (ddd, J=8.1, 7.0, 0.9 Hz, 1H), 4.65-4.52(m, 2H), 4.46-4.33 (m, 1H), 3.87-3.62 (m, 2H), 2.16-1.94 (m, 1H),1.93-1.65 (m, 3H).

Intermediate 110: 4-(4-Aminophenyl)-7-methoxyphthalazin-1(2H)-one, TFA

Intermediate 110A: Ethyl2-(4-((tert-butoxycarbonyl)amino)benzoyl)-5-methoxybenzoate

(4-((tert-Butoxycarbonyl)amino)phenyl)boronic acid (915 mg, 3.86 mmol),ethyl 2-bromo-5-methoxybenzoate (500 mg, 1.930 mmol), PEPPSI-IPRcatalyst (65.8 mg, 0.096 mmol), and Cs₂CO₃ (1886 mg, 5.79 mmol) wereplaced in a vial. PhCl (10 mL) was added, and the vial was evacuated andbackfilled with CO gas (3×). The mixture was heated with stirring at 80°C. under balloon of CO for 20 h. Most of PhCl was removed under reducedpressure, the residue was purified by flash chromatography (0-70%EtOAc/Hex) to afford Intermediate 110A (308 mg, 40% yield) as an amberoil, which solidified upon standing. MS(ESI) m/z: 400.2 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 9.78 (s, 1H), 7.67-7.57 (m, 2H), 7.48 (d, J=8.4Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.26 (dd,J=8.6, 2.6 Hz, 1H), 3.97 (q, J=7.1 Hz, 2H), 3.88 (s, 3H), 1.48 (s, 9H),0.98 (t, J=7.2 Hz, 3H).

Intermediate 110B: tert-Butyl(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate

Intermediate 110A (308 mg, 0.799 mmol) was placed in a pressure vial,and dioxane (4 mL), and hydrazine hydrate (0.581 mL, 12.0 mmol) wereadded sequentially. The reaction mixture was stirred at rt for 15 min,and then at 100° C. for 3 h. The reaction mixture was diluted with EtOAc(100 mL), washed with water (3×), brine, and dried (Na₂SO₄). The organicphase was concentrated and the residue was purified by flashchromatography (5-100% EtOAc/Hex) to afford Intermediate 110B (172 mg,59% yield) as a white solid. MS(ESI) m/z: 368.1 (M+H)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.69 (s, 1H), 9.56 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.66(d, J=8.8 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.49-7.42 (m, 3H), 3.95 (s,3H), 1.50 (s, 9H).

Intermediate 110

Intermediate 110B (172 mg, 0.468 mmol) was dissolved in TFA (2 mL), andthe reaction mixture was stirred at rt for 15 min. TFA was removed underreduced pressure, the residue triturated with Et₂O to give Intermediate110 (171 mg, 96% yield) as an off-white solid. MS(ESI) m/z: 268.1(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.65 (s, 1H), 7.71 (d, J=2.6Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.46 (dd, J=9.0, 2.9 Hz, 1H), 7.38 (d,J=8.6 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 3.95 (s, 3H).

Intermediate 111:N-(4-(3-(Dicyclopropylmethyl)-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

Intermediate 111A:4-(4-Bromophenyl)-2-(dicyclopropylmethyl)phthalazin-1(2H)-one

Ph₃P (4.35 g, 16.60 mmol) was dissolved in dry THF (40 mL), and thestirred reaction mixture was cooled to 0° C. Afterwards, DIAD (3.23 mL,16.60 mmol) was added dropwise over 5 min, and the reaction mixture wasstirred at 0° C. for 15 min (thick suspension formed). Then, asuspension of 4-(4-bromophenyl)phthalazin-1 (2H)-one (2.000 g, 6.64mmol) and dicyclopropylmethanol (0.979 mL, 8.30 mmol) in dry THF (20 mL)was added, and the reaction mixture was allowed to reach rt, and stirredat rt for 16 h. The reaction mixture was quenched with MeOH (5 mL),diluted with EtOAc (250 mL). Then CELITE® was added, the solvent wasremoved under reduced pressure and the residue was purified flashchromatography (EtOAc/hexane) to afford 1.396 g (53.2%) of Intermediate111A as a white solid. MS(ESI) m/z: 395.1 (M+H)⁺; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.56-8.47 (m, 1H), 7.85-7.72 (m, 3H), 7.71-7.63 (m, 2H),7.59-7.48 (m, 2H), 3.81 (t, J=9.2 Hz, 1H), 1.63-1.56 (m, 2H), 0.75-0.63(m, 2H), 0.57-0.46 (m, 2H), 0.43-0.30 (m, 4H).

Intermediate 111B:4-(4-Aminophenyl)-2-(dicyclopropylmethyl)phthalazin-1(2H)-one

The following reaction was carried out behind the blast shield.Intermediate 111A (1.396 g, 3.53 mmol), L-Proline (0.529 g, 4.59 mmol),and cuprous oxide (0.505 g, 3.53 mmol) were placed into a round-bottomflask, and DMSO (20 mL) was added. The reaction mixture was degassedwith stirring (3× vacuum/Ar), and sodium azide (0.459 g, 7.06 mmol) wasadded. The reaction mixture was degassed again (2× vacuum/Ar), andstirred under Ar at 100° C. for 3 h. The reaction mixture was cooled tort, was quenched with NH₄C₁ (std. aq, 10 mL), diluted with EtOAc (500mL) and water (200 mL). Organic phase was separated, washed with Na₂CO₃(aq. std., 2×50 mL), water (1×100 mL), brine (1×50 mL), dried (Na₂SO₄)and filtered. EtOAc was removed under reduced pressure and the residuewas purified by flash chromatography (EtOAc/hexane) to affordIntermediate 111B (0.742 g, 63.4% yield) as an off-white solid. MS(ESI)m/z: 332.1 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.34 (dd, J=8.1, 1.3Hz, 1H), 7.97-7.81 (m, 3H), 7.34 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.6 Hz,2H), 5.45 (s, 2H), 3.67 (t, J=9.0 Hz, 1H), 1.58-1.45 (m, 2H), 0.70-0.60(m, 2H), 0.55 (dq, J=9.4, 4.9 Hz, 2H), 0.40-0.29 (m, 2H), 0.18 (dq,J=9.4, 4.9 Hz, 2H).

Intermediate 111

1H-Pyrazole-4-carboxylic acid (0.301 g, 2.69 mmol) was suspended in DCM(20 mL), and a drop a DMF was added. Then, oxalyl chloride (2 M in DCM)(5.60 mL, 11.19 mmol) was added dropwise, and the reaction mixture wasstirred for 2 h at rt (reaction mixture became homogeneous). Then, DCMwas removed under reduced pressure, and the obtained acid chloride(white solid) was used in the subsequent step. In a separate flask, to asolution of Intermediate 111B (0.742 g, 2.239 mmol) in THF (20 mL), wasadded Trimethylsilyl cyanide (2.99 mL, 22.39 mmol). The resultantsolution was stirred at rt for 10 min, and then was treated with asolution of 1H-pyrazole-4-carboxylic acid chloride obtained as describedabove in THF (5 mL). The mixture was stirred at 50° C. for 1.5 h.Afterwards, the reaction mixture was concentrated, then trifluoroethanol(10 mL) was added. The mixture was stirred at 70° C. for 15 min, andthen concentrated. The obtained reside was purified by flashchromatography (MeOH/DCM) to give 0.781 g (82%) of Intermediate 111.MS(ESI) m/z: 426.1 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.29 (br.s., 1H), 10.01 (s, 1H), 8.37 (dd, J=7.5, 1.3 Hz, 1H), 8.27 (br. s., 1H),7.99-7.87 (m, 4H), 7.87-7.81 (m, 1H), 7.66 (d, J=8.6 Hz, 2H), 3.70 (t,J=9.2 Hz, 1H), 1.61-1.47 (m, 2H), 0.72-0.61 (m, 2H), 0.57 (dq, J=9.5,4.8 Hz, 2H), 0.42-0.31 (m, 2H), 0.20 (dq, J=9.6, 4.9 Hz, 2H)

Intermediate 112: 5-Methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 112A: Ethyl5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylate

To the solution of aniline (0.33 g, 3.54 mmol) in acetonitrile (6 mL) at0° C. was added isoamyl nitrite (0.524 mL, 3.90 mmol), followed byazidotrimethylsilane (0.513 mL, 3.90 mmol) dropwise. After 5 min, thecold bath removed, and the reaction was stirred at rt for 10 min, thenethyl but-2-ynoate (0.795 g, 7.09 mmol) added, and the reaction stirredin a sealed tube at 80° C. for 20 h, then cooled to rt. The reactionmixture was concentrated, then the residue was purified via preparativeHPLC to afford Intermediate 112A (50 mg, 6% yield). MS(ESI) m/z: 232.0(M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.63-7.55 (m, 3H), 7.49-7.41(m, 2H), 4.47 (q, J=7.0 Hz, 2H), 2.60 (s, 3H), 1.45 (t, J=7.2 Hz, 3H).

Intermediate 112

Intermediate 112A (36 mg, 0.16 mmol) was mixed with 1M lithium hydroxide(0.3 mL, 0.3 mmol) in THF (2 mL) and MeOH (2 mL), stirred rt for 2 h.The reaction mixture was concentrated and the residue was purified viapreparative HPLC to afford Intermediate 112 (26 mg, 82% yield). MS(ESI)m/z: 204.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 7.70-7.61 (m, 3H),7.60-7.52 (m, 2H), 2.59-2.54 (m, 3H).

Intermediate 113:1-(4-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

Intermediate 113A: Ethyl1-(4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylateIntermediate 113B: Ethyl1-(4-methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate

To the solution of 4-methoxyaniline (0.31 g, 2.5 mmol) in acetonitrile(6 mL) at 0° C. was added isoamyl nitrite (0.372 mL, 2.77 mmol),followed by azidotrimethylsilane (0.364 mL, 2.77 mmol) dropwise. After 5min, the cold bath removed, and the reaction was stirred at rt for 10min, then ethyl but-2-ynoate (0.564 g, 5.03 mmol) was added, and thereaction stirred in a sealed tube at 80° C. The reaction was stirred at80° C. for 20 h, then cooled to rt. The reaction mixture wasconcentrated, then the residue was purified via preparative HPLC toafford Intermediate 113A (60 mg, 9% yield) and Intermediate 113B (22 mg,3% yield).

Intermediate 113A

MS(ESI) m/z: 262.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.36-7.30(m, 2H), 7.06-7.00 (m, 2H), 4.43 (q, J=7.2 Hz, 2H), 3.86 (s, 3H), 2.53(s, 3H), 1.42 (t, J=7.2 Hz, 3H).

Intermediate 113B

MS(ESI) m/z: 262.2 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 7.37-7.31(m, 2H), 7.03-6.97 (m, 2H), 4.27 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 2.62(s, 3H), 1.25 (t, J=7.2 Hz, 3H).

Intermediate 113

Intermediate 113A (60 mg, 0.23 mmol) was mixed with 1M lithium hydroxide(0.5 mL, 0.5 mmol) in THF (1 mL) and MeOH (1 mL). The reaction mixturewas stirred rt for 3 h. The reaction mixture was concentrated and theresidue was purified via preparative HPLC to afford Intermediate 113 (48mg, 90% yield) as a white solid. MS(ESI) m/z: 234.0 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 7.48-7.41 (m, 2H), 7.17-7.11 (m, 2H), 3.88 (s, 3H),2.52 (s, 3H).

Intermediate 114:1-(4-Methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylic acid

Intermediate 113B (22 mg, 0.084 mmol) was mixed with 1M lithiumhydroxide (0.2 mL, 0.2 mmol) in THF (1 mL) and MeOH (1 mL) and wasstirred at rt for 2 h. The reaction mixture was concentrated and theresidue was acidified with TFA. The mixture was concentrated and theresidue was purified by flash chromatography (0-20% MeOH/DCM) to affordIntermediate 114. MS(ESI) m/z: 234.0 (M+H)⁺; ¹H NMR (400 MHz,methanol-d₄) δ 7.45-7.24 (m, 2H), 7.08-6.90 (m, 2H), 3.87 (s, 3H), 2.58(s, 3H).

Example 1:4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To 4-chlorophthalazin-1(2H)-one (9.9 mg, 0.055 mmol), Intermediate 8 (14mg, 0.050 mmol) and potassium phosphate (26.4 mg, 0.125 mmol), wereadded dioxane (3 mL) and water (0.5 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (2.9 mg, 2.5 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated, then was purified by preparative HPLC toafford 4.4 mg (18%) of Example 1. MS(ESI) m/z: 382.20 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.42-8.29 (m, 1H), 7.96-7.84 (m,2H), 7.77-7.67 (m, 1H), 7.61-7.52 (m, 2H), 7.52-7.43 (m, 2H), 7.41-7.36(m, 2H), 7.36-7.27 (m, 2H), 4.98 (s, 2H), 4.70 (s, 2H), 3.89 (s, 2H);Analytical HPLC RT=1.51 min (Method E), 1.52 min (Method F).

Example 2:4-(4-(2-(5-Fluoroisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According a method similar to the preparation of Example 1, substitutionof isoindoline with 5-fluoroisoindoline afforded Example 2. MS(ESI) m/z:400.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.38-8.31 (m,1H), 7.93-7.86 (m, 2H), 7.74-7.69 (m, 1H), 7.66-7.36 (m, 5H), 7.23 (d,J=9.1 Hz, 1H), 7.18-7.10 (m, 1H), 4.95 (d, J=16.8 Hz, 2H), 4.68 (d,J=16.8 Hz, 2H), 3.87 (s, 2H); Analytical HPLC RT=1.53 min (Method E),1.52 min (Method F).

Example 3:4-(4-(2-(5-Methoxyisoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a solution of Intermediate 1 (25 mg, 0.089 mmol) in DMF (3 mL), wasadded 5-methoxyisoindoline (20 mg, 0.134 mmol), PyBOP (69.6 mg, 0.134mmol), and DIEA (0.078 mL, 0.446 mmol). The mixture was stirred at rtfor 2 h, then was purified by preparative HPLC to afford 28.1 mg (59%)of Example 3. MS(ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.82 (s, 1H), 8.36-8.31 (m, 1H), 7.93-7.86 (m, 2H), 7.73-7.68 (m, 1H),7.55 (d, J=7.7 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 7.26 (dd, J=8.3, 4.4 Hz,1H), 6.95 (d, J=11.6 Hz, 1H), 6.88 (dd, J=8.4, 1.8 Hz, 1H), 4.95-4.86(m, 2H), 4.69-4.59 (m, 2H), 3.87 (s, 2H), 3.75 (s, 3H); Analytical HPLCRT=1.61 min (Method E), 1.61 min (Method F).

The following Examples in Table 1 were made by using the same procedureas shown in Example 3. Intermediate 1 was coupled with the appropriateamine. Various coupling reagents could be used other than the onedescribed in Example 3 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 1 LC HPLC MS Method, Ex- (M + RT ample R Name H)⁺ (min.) ¹H NMR 4

4-{4-[2-oxo-2-(1,2,3,4- tetrahydroisoquinolin- 2-yl)ethyl]phenyl}-1,2-dihydrophthalazin-1- one 396.1 E: 1.56 F: 1.55 (500 MHz, DMSO-d₆) δ12.92-12.70 (m, 1H), 8.34 (dd, J = 5.4, 2.1 Hz, 1H), 7.97-7.84 (m, 2H),7.75-7.56 (m, 1H), 7.56-7.47 (m, 2H), 7.47-7.34 (m, 2H), 7.25-7.05 (m,4H), 4.77 (s, 1H), 4.66 (s, 1H), 3.97-3.84 (m, 2H), 3.79 (t, J = 5.9 Hz,1H), 3.72 (t, J = 5.9 Hz, 1H), 2.79 (t, J = 5.9 Hz, 2H) 5

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(pyridin-3-yl)acetamide 357.1 E: 0.95 F: 1.13 (500 MHz, DMSO-d₆) δ 12.83 (s, 1H),10.69 (s, 1H), 8.92 (br. s., 1H), 8.41-8.30 (m, 2H), 8.19 (d, J = 8.5Hz, 1H), 7.94-7.83 (m, 2H), 7.75-7.66 (m, 1H), 7.60-7.55 (m, 2H), 7.55(d, J = 3.6 Hz, 1H), 7.54-7.50 (m, 2H), 3.83 (s, 2H) 6

N-benzyl-2-[4-(4-oxo- 3,4-dihydrophthalazin- 1-yl)phenyl]acetamide 370.1E: 1.50 F: 1.50 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.62 (t, J = 5.5 Hz,1H), 8.34 (dd, J = 6.3, 2.8 Hz, 1H), 7.95-7.83 (m, 2H), 7.78-7.63 (m,1H), 7.57-7.51 (m, J = 8.0 Hz, 2H), 7.49- 7.40 (m, J = 8.0 Hz, 2H),7.36-7.29 (m, 2H), 7.29-7.22 (m, 3H), 4.31 (d, J = 6.1 Hz, 2H), 3.60 (s,2H) 7

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(pyridin-4-yl)acetamide 357.1 E: 0.98 F: 1.13 (500 MHz, DMSO-d₆) δ 12.84 (s, 1H),11.39 (s, 1H), 8.65 (d, J = 6.3 Hz, 2H), 8.45-8.29 (m, 1H), 7.97 (d, J =6.6 Hz, 2H), 7.93-7.84 (m, 2H), 7.80-7.65 (m, 1H), 7.63-7.55 (m, J = 8.0Hz, 2H), 7.55-7.43 (m, J = 8.0 Hz, 2H), 3.93 (s, 2H) 8

N-benzyl-N-methyl-2- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 384.1 E: 1.54 F: 1.53 (500 MHz, DMSO-d₆) δ 12.83(br. s., 1H), 8.41-8.29 (m, 1H), 7.96-7.85 (m, 2H), 7.73-7.63 (m, 1H),7.60-7.14 (m, 9H), 4.81-4.50 (m, 2H), 3.95-3.82 (m, 2H), 3.10- 2.80 (m,3H) 9

N-(1H-1,3- benzodiazol-2-yl)-2-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 396.2 E: 1.09 F: 1.34 ¹H NMR (500 MHz, DMSO-d₆) δ12.83 (s, 1H), 12.03 (br. s., 1H), 8.37-8.29 (m, 1H), 7.93-7.85 (m, 2H),7.72- 7.66 (m, 1H), 7.61-7.53 (m, 4H), 7.47 (dd, J = 5.8, 3.3 Hz, 2H),7.14 (dd, J = 5.5, 3.0 Hz, 2H), 3.93 (s, 2H) 10

N-(1,3-benzoxazol-2- yl)-2-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 397.1 E: 1.29 F: 1.31 ¹H NMR (500 MHz, DMSO-d₆) δ12.82 (s, 1H), 8.34 (dd, J = 6.2, 2.9 Hz, 1H), 7.94-7.83 (m, 2H),7.76-7.67 (m, 1H), 7.58-7.45 (m, 5H), 7.26-7.20 (m, 1H), 7.20-7.15 (m,1H), 3.87 (br. s., 2H) 11

4-{4-[2-oxo-2-(4- phenylpiperidin-1- yl)ethyl]phenyl}-1,2-dihydrophthalazin-1- one 424.4 C: 2.63 D: 3.80 ¹H NMR (500 MHz, DMSO-d₆)δ 12.84 (br. s., 1H), 8.34 (d, J = 6.1 Hz, 1H), 7.88 (br. s., 2H), 7.68(d, J = 6.7 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.44 (d, J = 7.6 Hz, 2H),7.32-7.23 (m, 2H), 7.20 (d, J = 6.7 Hz, 3H), 4.58 (d, J = 11.3 Hz, 1H),4.13 (d, J = 12.8 Hz, 1H), 3.87 (br. s., 2H), 3.13 (t, J = 13.0 Hz, 1H),2.82-2.71 (m, 1H), 2.66 (t, J = 12.4 Hz, 1H), 1.77 (t, J = 14.5 Hz, 2H),1.51-1.34 (m, 2H) 12

4-{4-[2-(4- benzylpiperazin-1-yl)- 2-oxoethyl]phenyl}-1,2-dihydrophthalazin- 1-one 439.4 C: 2.41 D: 3.63 ¹H NMR (500 MHz,DMSO-d₆) δ 12.84 (br. s., 1H), 8.34 (br. s., 1H), 7.89 (d, J = 3.1 Hz,2H), 7.69 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 7.3 Hz, 2H), 7.39 (d, J =7.9 Hz, 2H), 7.35-7.19 (m, 5H), 3.81 (br. s., 2H), 3.57-3.45 (m, 6H),2.31 (br. s., 4H) 13

4-(4-{2-[(2S)-2- (methoxymethyl) pyrrolidin-2-yl]-2-oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 378.4 C: 2.13 D: 3.24 ¹HNMR (500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H), 8.34 (d, J = 6.1 Hz, 1H),7.90 (br. s., 2H), 7.70 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 6.1 Hz, 2H),7.40 (d, J = 7.0 Hz, 2H), 4.08 (br. s., 1H), 3.78-3.68 (m, 2H), 3.23(br. s., 3H), 2.00-1.76 (m, 5H) 14

N-(cyclopropylmethyl)- 2-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 334.3 C: 1.94 D: 3.05 ¹H NMR (400 MHz, CD₃OD)/CDCl₃(1:1)) δ 8.43 (dt, J = 4.3, 2.4 Hz, 1H), 7.84-7.64 (m, 3H), 7.55-7.46(m, 2H), 7.42 (d, J = 8.0 Hz, 2H), 3.59 (s, 2H), 3.05 (d, J = 7.0 Hz,2H), 0.98-0.81 (m, 1H), 0.50-0.36 (m, 2H), 0.19- 0.07 (m, 2H) 15

4-(4-{2-oxo-2-[4- (pyrimidin-2-yl) pipereazin-1-yl]ethyl} phenyl)-1,2-dihydrophthalazin-1- one 427.4 C: 2.10 D: 3.26 ¹H NMR (500 MHz, DMSO-d₆)δ 12.83 (br. s., 1H), 8.44- 8.28 (m, 3H), 7.89 (d, J = 3.7 Hz, 2H), 7.69(br. s., 1H), 7.54 (d, J = 7.3 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H),6.70-6.62 (m, 1H), 3.89 (br. s., 2H), 3.72 (br. s., 4H), 3.65 (br. s.,2H), 3.59 (br. s., 2H) 16

4-(4-{2-[4-(4- methoxyphenyl) piperazin-1-yl]-2- oxoethyl}phenyl)-1,2-dihydrophthalazin-1- one 455.4 C: 2.23 D: 3.47 ¹H NMR (500 MHz, DMSO-d₆)δ 12.83 (br. s., 1H), 8.33 (br. s., 1H), 7.88 (br. s., 2H), 7.68 (br.s., 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.6 Hz, 2H), 6.95-6.85(m, 2H), 6.82 (d, J = 8.5 Hz, 2H), 3.88 (br. s., 2H), 3.68 (br. s., 4H),3.64 (br. s., 2H), 2.96 (br. s., 4H) 17

4-{4-[2-(4- benzylpiperidin-1-yl)- 2-oxoethyl]phenyl}-1,2-dihydrophthalazin- 1-one 438.4 C: 2.77 D: 4.04 ¹H NMR (500 MHz,DMSO-d₆) δ 12.84 (br. s., 1H), 8.34 (br. s., 1H), 7.90 (d, J = 3.7 Hz,2H), 7.69 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.39 (d, J =7.6 Hz, 2H), 7.30-7.21 (m, 2H), 7.21-7.10 (m, 3H), 4.38 (d, J = 13.1 Hz,1H), 3.98 (d, J = 11.6 Hz, 1H), 3.80 (br. s., 2H), 2.96 (t, J = 12.4 Hz,1H), 1.75 (br. s., 1H), 1.56 (br. s., 2H), 0.99 (t, J = 10.2 Hz, 2H) 18

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-[(1S,2R)-2-phenylcyclopropyl] acetamide 396.4 C: 2.35 D: 3.56 ¹H NMR (500 MHz,DMSO-d₆) δ 12.84 (br. s., 1H), 8.49 (br. s., 1H), 8.34 (br. s., 1H),7.90 (d, J = 3.7 Hz, 2H), 7.71 (d, J = 5.5 Hz, 1H), 7.54 (d, J = 7.6 Hz,2H), 7.44 (d, J = 7.3 Hz, 2H), 7.29-7.21 (m, 2H), 7.19-7.06 (m, 3H),3.52 (br. s., 2H), 2.85 (br. s., 1H), 1.97 (br. s., 1H), 1.18 (d, J =5.8 Hz, 2H) 19

N-cyclobutyl-2-[4-(4- oxo-3,4- dihydrophthalazin-1- yl)phenyl]acetamide334.3 C: 1.95 D: 3.11 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),8.40 (d, J = 6.1 Hz, 1H), 8.33 (br. s., 1H), 7.89 (d, J = 3.4 Hz, 2H),7.69 (d, J = 6.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.9 Hz,2H), 4.25-4.11 (m, 1H), 3.46 (s, 2H), 2.22- 2.11 (m, 2H), 1.96-1.83 (m,2H), 1.70-1.55 (m, 2H) 20

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N- phenylacetamide356.3 C: 2.21 D: 3.36 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (br. s., 1H),10.25 (br. s., 1H), 8.33 (br. s., 1H), 7.88 (d, J = 4.0 Hz, 2H), 7.70(br. s., 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.59-7.46 (m, 4H), 7.34-7.25 (m,2H), 7.09-6.99 (m, 1H), 3.76 (br. s., 2H) 21

N-(1,3-benzothiazol-6- yl)-2-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 413.4 C: 1.96 D: 3.20 ¹H NMR (500 MHz, DMSO-d₆) δ12.85 (br. s., 1H), 10.65 (br. s., 1H), 9.26 (br. s., 1H), 8.58 (br. s.,1H), 8.33 (br. s., 1H), 8.02 (d, J = 8.9 Hz, 1H), 7.89 (br. s., 2H),7.71 (br. s., 1H), 7.65 (d, J = 9.5 Hz, 1H), 7.55 (br. s., 4H), 3.82(br. s., 2H) 22

N-methyl-2-[4-(4-oxo- 3,4-dihydrophthalazin- 1-yl)phenyl]-N-phenylacetamide 370.3 C: 2.25 D: 3.52 ¹H NMR (500 MHz, DMSO-d₆) δ 12.83(br. s., 1H), 8.33 (d, J = 6.7 Hz, 1H), 7.89 (br. s., 2H), 7.73-7.62 (m,J = 7.3 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.47 (br. s., 3H), 7.39 (d, J= 7.9 Hz, 4H), 7.20 (br. s., 1H), 3.51 (br. s., 2H), 3.21 (br. s., 3H)23

4-{4-[2-(2,3-dihydro- 1H-indol-1-yl)-2- oxoethyl]phenyl}-1,2-dihydrophthalazin-1- one 382.3 C: 2.48 D: 3.67 ¹H NMR (500 MHz, DMSO-d₆)δ 12.85 (br. s., 1H), 8.34 (d, J = 7.3 Hz, 1H), 8.08 (d, J = 7.6 Hz,1H), 7.96-7.84 (m, 2H), 7.72 (d, J = 7.3 Hz, 1H), 7.59-7.51 (m, 2H),7.47 (d, J = 7.0 Hz, 2H), 7.24 (d, J = 6.4 Hz, 1H), 7.18-7.10 (m, 1H),7.00 (t, J = 6.6 Hz, 1H), 4.26-4.17 (m, 2H), 3.96 (br. s., 2H),3.20-3.14 (m, J = 9.2 Hz, 2H) 24

N-(2,3-dihydro-1,4- benzodioxin-6-yl)-2-[4- (4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]acetamide 414.3 C: 2.13 D: 3.25 ¹H NMR(500 MHz, DMSO-d₆) δ 12.84 (br. s., 1H), 10.09 (br. s., 1H), 8.39-8.27(m, 1H), 7.89 (d, J = 2.4 Hz, 2H), 7.74-7.65 (m, 1H), 7.58-7.51 (m, 2H),7.49 (d, J = 6.7 Hz, 2H), 7.26 (br. s., 1H), 6.99 (d, J = 6.4 Hz, 1H),6.78 (d, J = 8.9 Hz, 1H), 4.20 (d, J = 6.4 Hz, 4H), 3.70 (br. s., 2H) 25

4-[4-(2-{5-[(4- methylpiperazin-1- yl)methyl]-2,3-dihydro-1H-isoindol-2-yl}-2- dihydrophthalazin-1- one 494.3 E: 0.94 F: 1.15 ¹HNMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.37-8.30 (m, 1H), 7.93-7.86 (m,2H), 7.71 (d, J = 7.2 Hz, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.47 (d, J =7.7 Hz, 2H), 7.33-7.25 (m, 2H), 7.23 (d, J = 7.7 Hz, 1H), 4.95 (d, J =7.4 Hz, 2H), 4.67 (d, J = 4.7 Hz, 2H), 3.87 (s, 2H), 3.46 (d, J = 3.3Hz, 2H), 2.36 (br. s., 8H), 2.17 (br. s., 3H) 26

N-(3-methyl-1,2- oxazol-5-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 361.2 C: 2.06 D: 3.11 ¹H NMR (500 MHz, DMSO-d₆) δ12.84 (br. s., 1H), 8.33 (br. s., 1H), 7.89 (br. s., 2H), 7.69 (br. s.,1H), 7.56 (d, J = 7.3 Hz, 2H), 7.48 (d, J = 4.9 Hz, 2H), 6.12 (br. s.,1H), 3.82 (br. s., 2H), 2.17 (br. s., 3H) 27

N-(5-methyl-1,2- oxazol-3-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 361.2 C: 2.06 D: 3.08 ¹H NMR (500 MHz, DMSO-d₆) δ12.84 (br. s., 1H), 11.21 (br. s., 1H), 8.33 (br. s., 1H), 7.89 (d, J =3.1 Hz, 2H), 7.70 (br. s., 1H), 7.55 (d, J = 7.3 Hz, 2H), 7.49 (d, J =7.0 Hz, 2H), 6.62 (br. s., 1H), 3.78 (br. s., 2H), 2.36 (br. s., 3H) 28

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(1,3-thiazol-2-yl)acetamide 363.2 C: 2.07 D: 3.13 ¹H NMR (400 MHz, DMSO-d₆) δ12.86 (br. s., 1H), 8.36- 8.30 (m, 1H), 7.93-7.86 (m, 2H), 7.73-7.69 (m,1H), 7.58-7.53 (m, 2H), 7.53-7.48 (m, 2H), 7.42 (d, J = 3.5 Hz, 1H),7.09 (br. s., 1H), 3.83 (s, 2H) 29

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(1,3,4- thiadiazol-2-yl)acetamide 364.2 C: 1.84 D: 2.87 ¹H NMR (400 MHz, DMSO-d₆) δ 12.85 (s,1H), 9.11 (s, 1H), 8.37-8.30 (m, 1H), 7.95-7.85 (m, 2H), 7.74-7.68 (m,1H), 7.59-7.53 (m, 2H), 7.53-7.48 (m, 2H), 3.92 (s, 2H) 30

N-(6-chloropyridazin- 3-yl)-2-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 392.2 C: 2.12 D: 3.18 ¹H NMR (400 MHz, DMSO-d₆) δ12.86 (br. s., 1H), 11.67 (br. s., 1H), 8.40 (d, J = 9.5 Hz, 1H),8.36-8.30 (m, 1H), 7.94-7.85 (m, 3H), 7.74-7.66 (m, 1H), 7.60-7.55 (m,2H), 7.55-7.49 (m, 2H), 3.92 (s, 2H) 31

N-(5-methyl-1,3,4- thiadiazol-2-yl)-2-[4- (4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]acetamide 378.2 C: 1.81 D: 3.07 ¹H NMR(400 MHz, DMSO-d₆) δ 12.86 (s, 1H), 12.70 (br. s., 1H), 8.36-8.30 (m,1H), 7.93-7.85 (m, 2H), 7.75- 7.66 (m, 1H), 7.60-7.53 (m, 2H), 7.53-7.46(m, 2H), 3.92 (s, 2H), 2.60 (s, 3H) 32

4-{4-[2-(5-methyl-2,3- dihydro-1H-indol-1- yl)-2-oxoethyl] phenyl}-1,2-dihydrophthalazin-1- one 396.1 A: 9.56 B: 9.14 (500 MHz, DMSO-d₆) δ12.83 (s, 1H), 8.41-8.29 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 7.91-7.85(m, 2H), 7.73-7.68 (m, 1H), 7.62-7.52 (m, J = 8.3 Hz, 2H), 7.48-7.42 (m,J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.95 (d, J = 8.3 Hz, 1H), 4.21 (t, J =8.5 Hz, 2H), 3.94 (s, 2H), 3.14 (t, J = 8.4 Hz, 2H), 2.25 (s, 3H) 33

4-{4-[2-(6-ethoxy-2,3- dihydro-1H-indol-1- yl)-2-oxoethyl] phenyl}-1,2-dihydrophthalazin-1- one 426.1 A: 9.62 B: 9.23 (500 MHz, DMSO-d₆) δ12.83 (s, 1H), 8.42-8.30 (m, 1H), 7.94-7.84 (m, 2H), 7.80-7.65 (m, 2H),7.62-7.51 (m, J = 8.0 Hz, 2H), 7.51-7.40 (m, J = 8.3 Hz, 2H), 7.11 (d, J= 8.0 Hz, 1H), 6.56 (dd, J = 8.0, 2.5 Hz, 1H), 4.24 (t, J = 8.3 Hz, 2H),4.02-3.89 (m, 4H), 3.09 (t, J = 8.3 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H) 34

4-{4-[2-oxo-2-[6- tetrahydroquinolin-1- yl)ethyl]phenyl}-1,2-dihydrophthalazin-1- one 450.2 E: 1.91 F: 1.73 (500 MHz, DMSO-d₆) δ12.81 (s, 1H), 8.37-8.29 (m, 1H), 7.95-7.87 (m, 2H), 7.66 (d, J = 7.7Hz, 1H), 7.49 (d, J = 7.7 Hz, 3H), 7.33 (br. s., 2H), 7.19 (d, J = 6.9Hz, 2H), 7.13 (d, J = 7.2 Hz, 1H), 3.99 (s, 2H), 3.75 (t, J = 6.2 Hz,2H), 2.66 (br. s., 2H), 1.86 (quin, J = 6.5 Hz, 2H) 35

4-(4-{2-oxo-2-[6- (trifluoromethyl)-2,3- dihydro-1H-indol-1-yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 450.2 E: 1.91 F: 1.96(500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.42-8.30 (m, 2H), 7.98-7.84 (m,2H), 7.80-7.67 (m, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.3 Hz,3H), 7.37 (d, J = 7.7 Hz, 1H), 4.32 (t, J = 8.5 Hz, 2H), 4.01 (s, 2H),3.29-3.24 (m, 2H) 39

4-{4-[2-(3,3-dimethyl- 2,3-dihydro-1H-indol- 1-yl)-2-oxoethyl]phenyl}-1,2- dihydrophthalazin-1- one 410.15 E: 1.88 F: 1.89 (500 MHz,DMSO-d₆) δ 12.85 (br. s., 1H), 8.38-8.32 (m, 1H), 8.06 (d, J = 8.4 Hz,1H), 7.93-7.86 (m, 2H), 7.76- 7.68 (m, 1H), 7.61-7.53 (m, J = 8.4 Hz,2H), 7.50-7.44 (m, J = 7.9 Hz, 2H), 7.27 (d, J = 7.4 Hz, 1H), 7.17 (t, J= 7.4 Hz, 1H), 7.08-7.00 (m, 1H), 3.98 (d, J = 8.9 Hz, 4H), 1.31 (s, 6H)40

4-{4-[2-(2-methyl-2,3- dihydro-1H-indol-1- yl)-2-oxoethyl] phenyl}-1,2-dihydrophthalazin-1- one 396.15 E: 1.75 F: 1.77 (500 MHz, CD₃OD) δ8.47-8.41 (m, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.88-7.77 (m, 3H),7.63-7.55 (m, 3H), 7.49 (d, J = 7.4 Hz, 2H), 7.25-7.17 (m, 2H), 7.06 (t,J = 7.4 Hz, 1H), 4.05 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 15.9 Hz, 1H),3.43 (dd, J = 15.6, 8.7 Hz, 1H), 2.72 (d, J = 15.4 Hz, 1H), 1.38 (d, J =5.9 Hz, 3H), 1.29 (br. s., 1H) 41

4-{4-[2-(6-methoxy- 2,3-dihydro-1H-indol- 1-yl)-2-oxoethyl] phenyl}-1,2-dihydrophthalazin-1- one 412.0 A: 8.50 B: 7.65 (500 MHz, DMSO-d₆) δ12.83 (s, 1H), 8.45-8.27 (m, 1H), 7.94-7.85 (m, 2H), 7.79-7.67 (m, 2H),7.63-7.53 (m, J = 8.0 Hz, 2H), 7.52-7.43 (m, J = 8.0 Hz, 2H), 7.13 (d, J= 8.3 Hz, 1H), 6.58 (dd, J = 8.3, 2.2 Hz, 1H), 4.25 (t, J = 8.4 Hz, 2H),3.96 (s, 2H), 3.70 (s, 3H), 3.10 (t, J = 8.4 Hz, 2H)

Example 36:2-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(isoindolin-2-yl)ethanone

To a vial containing Intermediate 4 (34.8 mg, 0.091 mmol),4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium phosphate(44 mg, 0.21 mmol), were added dioxane (0.9 mL) and water (0.1 mL). Themixture was degassed (evacuated and flushed with Ar (3×)). To thismixture was added Pd(Ph₃P)₄ (4.8 mg, 4.2 mmol). The mixture was degassed(3×), then the vial was sealed. The vial was heated in a microwavereactor at 150° C. for 25 min. The mixture was concentrated, then wasdiluted with 4 mL 1:1 DMSO/MeOH. TFA (0.1 mL) was added, then thesuspension was filtered and the solid collected. The solid was washedwith H₂O (˜5 mL), then MeOH (˜5 mL), sucked dry and dried in vacuo toafford 34.8 mg (42%) of Example 36 as a white solid. MS(ESI) m/z: 400.0(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H), 8.38-8.32 (m, 1H),7.92 (quind, J=7.1, 1.7 Hz, 2H), 7.76-7.71 (m, 1H), 7.51 (t, J=7.8 Hz,1H), 7.43 (dd, J=10.5, 1.4 Hz, 1H), 7.41-7.37 (m, 3H), 7.35-7.30 (m,2H), 5.02 (s, 2H), 4.71 (s, 2H), 3.92 (s, 2H); HPLC RT=7.96 min (MethodA), 8.02 min (Method B).

Example 37:4-(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a vial containing Intermediate 5 (34.8 mg, 0.091 mmol),4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium phosphate(44.1 mg, 0.208 mmol), were added dioxane (0.9 mL) and water (0.1 mL).The mixture was degassed (evacuated and flushed with Ar (3×)). To thismixture was added Pd(Ph₃P)₄ (4.8 mg, 4.15 μmol). The mixture wasdegassed (3×), then the vial was sealed. The vial was heated in amicrowave reactor at 150° C. for 25 min. The reaction mixture separatedinto two phases upon cooling. The organic phase was collected and waspurified by preparative HPLC to afford 11.7 mg (35%) of Example 37.MS(ESI) m/z: 400.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.94 (br. s.,1H), 8.37-8.29 (m, 1H), 7.92-7.86 (m, 2H), 7.65-7.49 (m, 4H), 7.45-7.28(m, 4H), 4.99 (s, 2H), 4.71 (s, 2H), 3.93 (s, 2H); HPLC RT=1.56 min(Method E), 1.52 min (Method F).

Example 38: 4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 36, couplingof Intermediate 6 (30 mg, 0.13 mmol) and Intermediate 9 (51 mg, 0.14mmol) afforded 17 mg (33%) of Example 38. MS(ESI) m/z: 381.1 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 11.43 (d, J=5.8 Hz, 1H), 8.29 (dd, J=8.1, 1.2Hz, 1H), 7.69 (td, J=7.7, 1.4 Hz, 1H), 7.61-7.51 (m, 2H), 7.44-7.35 (m,6H), 7.33-7.28 (m, 2H), 7.08 (s, 1H), 4.97 (s, 2H), 4.69 (s, 2H), 3.84(s, 2H); HPLC RT=8.20 min (Method A), 7.53 min (Method B).

Example 42: 4-(4-(1-(Indolin-1-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 3, coupling ofIntermediate 11 (13 mg, 0.044 mmol) and indoline (7.9 mg, 0.066 mmol)using HATU afforded 8.2 mg (46%) of Example 42. MS(ESI) m/z: 396.15(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H), 8.38-8.30 (m, 1H),8.18 (d, J=8.4 Hz, 1H), 7.92-7.84 (m, 2H), 7.74-7.68 (m, 1H), 7.62-7.55(m, J=8.4 Hz, 2H), 7.55-7.49 (m, J=8.4 Hz, 2H), 7.20 (d, J=7.4 Hz, 1H),7.16 (t, J=7.7 Hz, 1H), 7.02-6.94 (m, 1H), 4.37 (td, J=10.4, 6.4 Hz,1H), 4.23 (q, J=6.4 Hz, 1H), 3.91-3.75 (m, 1H), 3.16-3.00 (m, 2H), 1.46(d, J=6.4 Hz, 3H); HPLC RT=1.77 min (Method E), 1.75 min (Method F).

Example 43:4-(4-(1-(Isoindolin-2-yl)-1-oxopropan-2-yl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 3, coupling ofIntermediate 11 (13 mg, 0.044 mmol) and isoindoline (7.9 mg, 0.066 mmol)using HATU afforded 9.0 mg (52%) of Example 43. MS(ESI) m/z: 396.15(M+H)⁺; ¹H NMR (500 MHz, 1:1 CD₃OD/CDCl₃) δ 8.49-8.43 (m, 1H), 7.90-7.83(m, 2H), 7.83-7.78 (m, 1H), 7.61-7.58 (m, 2H), 7.57-7.52 (m, 2H),7.35-7.23 (m, 4H), 5.04 (d, J=13.9 Hz, 1H), 4.92-4.85 (m, 1H), 4.83-4.77(m, 1H), 4.66 (d, J=13.9 Hz, 1H), 4.09 (q, J=6.9 Hz, 1H), 1.58 (d, J=6.9Hz, 3H).

Example 44:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

Example 44A: N-(4-Bromophenyl)-2,3-dihydro-1H-indene-2-carboxamide

To a solution of 2,3-dihydro-1H-indene-2-carboxylic acid (141 mg, 0.872mmol) in DMF (3 mL), were added 4-bromoaniline (150 mg, 0.872 mmol),PyBOP (499 mg, 0.959 mmol), and DIEA (0.457 mL, 2.62 mmol). The mixturewas stirred at rt for 16 h. The reaction mixture was concentrated andthe residue was dissolved in EtOAc, washed with 10% LiCl, 1N HCl andbrine. The crude product was purified via flash chromatography to afford90 mg (33%) of Example 44A. MS(ESI) m/z: 316.0 (M+H)⁺.

Example 44B:N-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,3-dihydro-1H-indene-2-carboxamide

A mixture of Example 44A (62 mg, 0.20 mmol), bis(pinacolato)diboron(74.7 mg, 0.294 mmol), and potassium acetate (57.7 mg, 0.588 mmol) indioxane (3 mL) was degassed (3× vacuum/Ar). PdCl₂(dppf) CH₂Cl₂ adduct(4.3 mg, 5.9 μmol) was added. The reaction mixture was degassed again(3× vacuum/Ar), sealed in a vial and heated at 110° C. for 2 h. Thereaction mixture was filtered and concentrated to afford 40 mg (56%) ofExample 44B, which was used as is in the following step. MS(ESI) m/z:364.2 (M+H)⁺.

Example 44

To 4-chlorophthalazin-1(2H)-one (28.3 mg, 0.157 mmol), Example 44B (40mg, 0.11 mmol) and potassium phosphate (76 mg, 0.36 mmol), were addeddioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (8.2 mg, 7.1 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 25 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to yield 17.1 mg(24%) of Example 44. MS(ESI) m/z: 382.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.85(m, 2H), 7.84-7.79 (m, J=8.5 Hz, 2H), 7.76-7.69 (m, 1H), 7.59-7.50 (m,J=8.5 Hz, 2H), 7.24 (dd, J=5.1, 3.4 Hz, 2H), 7.15 (dd, J=5.4, 3.2 Hz,2H), 3.46 (t, J=8.5 Hz, 1H), 3.21 (dd, J=8.4, 3.2 Hz, 4H); HPLC RT=1.67min (Method E), 1.66 min (Method F).

Example 45:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-2-(pyridin-4-yl)thiazole-4-carboxamide

To a mixture of Intermediate 3 (25 mg, 0.105 mmol),2-(pyridin-4-yl)thiazole-4-carboxylic acid (44 mg, 0.21 mmol), and HATU(60 mg, 0.16 mmol) in THF (1 mL), were added DIEA (0.046 mL, 0.26 mmol)and DMF (1 mL). The mixture was stirred at rt for 2 h, then wasconcentrated. The crude product was purified via preparative HPLC toafford 25 mg (36%) of Example 45. MS(ESI) m/z: 426.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.84 (s, 1H), 10.53 (s, 1H), 8.86 (d, J=4.1 Hz, 2H),8.73 (s, 1H), 8.44-8.32 (m, 1H), 8.25 (d, J=6.1 Hz, 2H), 8.12-8.02 (m,2H), 7.97-7.86 (m, 2H), 7.82-7.76 (m, 1H), 7.68-7.60 (m, 2H); HPLCRT=5.13 min (Method A), 5.69 min (Method B).

The following Examples in Table 2 were made by using the same procedureas shown in Example 45. Intermediate 3 was coupled with the appropriatecarboxylic acid. Various coupling reagents could be used other than theone described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.

TABLE 2 LC HPLC MS Method, Ex- (M + RT ample R Name H)⁺ (min.) ¹H NMR 46

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide 425.1 E: 1.83 F: 1.88 (500 MHz, DMSO-d₆) δ 12.83(br. s., 1H), 10.44 (br. s., 1H), 8.58-8.51 (m, 1H), 8.35 (dd, J = 7.6,1.2 Hz, 1H), 8.18 (dd, J = 7.6, 2.1 Hz, 2H), 8.11-8.04 (m, J = 8.5 Hz,2H), 8.00-7.86 (m, 2H), 7.78 (d, J = 7.4 Hz, 1H), 7.66- 7.61 (m, J = 8.5Hz, 2H), 7.61-7.55 (m, 3H) 47

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5-(pyridin-4-yl)-1,3-thiazole-2- carboxamide 426.0 E: 1.11 F: 1.52 (500 MHz, DMSO-d₆)δ 12.85 (s, 1H), 10.91 (s, 1H), 8.96 (s, 1H), 8.82 (d, J = 5.8 Hz, 2H),8.40-8.33 (m, 1H), 8.30 (d, J = 5.8 Hz, 2H), 8.09-8.01 (m, J = 8.5 Hz,2H), 7.96-7.87 (m, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.71- 7.63 (m, J = 8.5Hz, 2H) 48

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2-[4- (trifluoromethyl)phenyl]-1,3-thiazole-4- carboxamide 493.2 E: 1.98 F: 1.99 (500 MHz,DMSO-d₆) δ 12.83 (s, 1H), 10.52 (s, 1H), 8.64 (s, 1H), 8.41 (d, J = 8.3Hz, 2H), 8.38-8.32 (m, 1H), 8.10-8.03 (m, J = 8.5 Hz, 2H), 7.98-7.86 (m,4H), 7.81-7.74 (m, 1H), 7.67-7.56 (m, J = 8.5 Hz, 2H) 49

2-(3,5-difluorophenyl)- N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1,3-thiazole- 4-carboxamide 461.2 E: 1.87 F: 1.88 ¹H NMR (500MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.51 (s, 1H), 8.77-8.68 (m, 1H), 8.63(s, 1H), 8.35 (dd, J = 7.6, 1.2 Hz, 1H), 8.13-8.02 (m, J = 8.5 Hz, 2H),7.98-7.85 (m, 2H), 7.81-7.74 (m, 1H), 7.65-7.61 (m, J = 8.5 Hz, 2H),7.58 (ddd, J = 11.6, 9.2, 2.3 Hz, 1H), 7.45-7.34 (m, 1H) 50

4-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1,3-thiazole-2-carboxamide 363.2 E: 1.46 F: 1.47 (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),10.91 (s, 1H), 8.34 (dd, J = 7.6, 1.5 Hz, 1H), 8.10-8.00 (m, J = 8.8 Hz,2H), 7.91 (td, J = 7.4, 1.4 Hz, 2H), 7.78-7.70 (m, 2H), 7.63-7.53 (m, J= 8.5 Hz, 2H), 2.53 (s, 3H) 51

5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-4H,5H,6H,7H-[1,3]thiazolo[5,4-c] pyridine-2-carboxamide 418.2 E: 0.98 F: 1.31(500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.92 (s, 1H), 8.34 (d, J = 7.2 Hz,1H), 8.08-8.00 (m, J = 8.5 Hz, 2H), 7.96-7.84 (m, 2H), 7.74 (d, J = 7.7Hz, 1H), 7.63-7.54 (m, J = 8.5 Hz, 2H), 3.72 (s, 2H), 2.97-2.92 (m, 2H),2.83-2.76 (m, 2H), 2.42 (s, 3H) 52

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-imidazole-2- carboxamide 346.2 E: 1.03 F: 1.26 (500 MHz, DMSO-d₆) δ12.81 (s, 1H), 10.55 (s, 1H), 8.38-8.29 (m, 1H), 8.06-7.98 (m, J = 8.5Hz, 2H), 7.94- 7.86 (m, 2H), 7.75 (d, J = 7.4 Hz, 1H), 7.62-7.53 (m, J =8.5 Hz, 2H), 7.47 (s, 1H), 7.11 (s, 1H), 4.02 (s, 3H) 53

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4,5,6,7-tetrahydro-1,3- benzothiazole-2- carboxamide 403.15 E: 1.70 F: 1.71 (500MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.85 (s, 1H), 8.34 (dd, J = 7.6, 1.2 Hz,1H), 8.07-8.01 (m, J = 8.5 Hz, 2H), 7.96-7.85 (m, 2H), 7.74 (d, J = 7.4Hz, 1H), 7.63- 7.53 (m, J = 8.5 Hz, 2H), 2.87 (dt, J = 15.7, 5.8 Hz,4H), 1.91-1.77 (m, 4H) 54

1-(4-nitrophenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]piperidine-4- carboxamide 470.25 E: 1.61 F: 1.62 (500 MHz,DMSO-d₆) δ 12.78 (s, 1H), 10.05 (s, 1H), 8.35-8.31 (m, 1H), 7.89 (td, J= 4.6, 1.8 Hz, 2H), 7.79- 7.75 (m, J = 8.5 Hz, 2H), 7.75-7.68 (m, 1H),7.55-7.47 (m, J = 8.5 Hz, 2H), 7.37-7.29 (m, 4H), 7.27-7.20 (m, 1H),3.48 (s, 2H), 2.96-2.84 (m, 2H), 2.41-2.29 (m, 1H), 1.98 (t, J = 11.1Hz, 2H), 1.84-1.75 (m, 2H), 1.75- 1.64 (m, 2H) 55

1-acetyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]piperidine-4-carboxamide 391.2 E: 1.06 F: 1.07 (500 MHz, DMSO-d₆) δ 12.78 (s, 1H),10.13 (s, 1H), 8.35-8.30 (m, 1H), 7.96-7.86 (m, 2H), 7.82-7.75 (m, J =8.5 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.56-7.47 (m, J = 8.5 Hz, 2H),4.42 (d, J = 13.2 Hz, 1H), 3.89 (d, J = 12.1 Hz, 1H), 3.09 (t, J = 12.0Hz, 1H), 2.66-2.58 (m, 2H), 1.84 (t, J = 13.1 Hz, 2H), 1.69-1.57 (m,1H), 1.53- 1.39 (m, 1H) 56

1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]piperidine-4-carboxamide 439.3 E: 1.05 F: 1.15 (500 MHz, DMSO-d₆) δ 12.78 (s, 1H),10.05 (s, 1H), 8.35-8.31 (m, 1H), 7.89 (td, J = 4.6, 1.8 Hz, 2H), 7.79-7.75 (m, J = 8.5 Hz, 2H), 7.75-7.68 (m, 1H), 7.55-7.47 (m, J = 8.5 Hz,2H), 7.37-7.29 (m, 4H), 7.27-7.20 (m, 1H), 3.48 (s, 2H), 2.96-2.84 (m,2H), 2.41-2.29 (m, 1H), 1.98 (t, J = 11.1 Hz, 2H), 1.84-1.75 (m, 2H),1.75- 1.64 (m, 2H) 57

1-(2-methoxyethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrrolidine-3- carboxamide 393.2 E: 1.01 F: 0.99 (500 MHz,DMSO-d₆) δ 10.14 (br. s., 1H), 8.33 (d, J = 7.4 Hz, 1H), 7.94-7.86 (m,2H), 7.80-7.74 (m, J = 8.3 Hz, 2H), 7.72 (d, J = 7.2 Hz, 1H), 7.57-7.46(m, J = 8.3 Hz, 2H), 3.45 (t, J = 5.5 Hz, 3H), 3.26 (s, 3H), 3.12-3.03(m, 1H), 2.96 (br. s., 1H), 2.73 (br. s., 1H), 2.63 (br. s., 3H), 2.01(d, J = 6.9 Hz, 2H) 58

4-(dimethylamino)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]benzamide 385.3 E: 1.38 F: 1.59 (500 MHz, DMSO-d₆) δ 12.80 (s,1H), 10.07 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.97-7.86 (m, 6H), 7.76(d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H),3.01 (s, 6H) 59

1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]pyrrolidine-3-carboxamide 425.25 E: 1.16 F: 1.26 (500 MHz, DMSO-d₆) δ 12.79 (s, 1H),10.11 (br. s., 1H), 8.39-8.29 (m, 1H), 7.93-7.86 (m, 2H), 7.79- 7.73 (m,J = 8.5 Hz, 2H), 7.72-7.67 (m, 1H), 7.54-7.48 (m, J = 8.5 Hz, 2H),7.40-7.31 (m, 4H), 7.28 (br. s., 1H), 3.67 (br. s., 2H), 3.14 (br. s.,1H), 2.96 (br. s., 1H), 2.82-2.69 (m, 2H), 2.59 (br. s., 1H), 2.07 (br.s., 2H) 60

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4-(pyrrolidin-1-yl)benzamide 411.2 E: 1.76 F: 1.74 (500 MHz, DMSO-d₆) δ 12.80 (s, 1H),10.03 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.97 (s, 2H), 7.93-7.86 (m,4H), 7.77 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 6.62 (d, J =8.5 Hz, 2H), 1.99 (br. s., 4H) 61

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4-(piperidin-1-yl)benzamide 425.25 E: 1.23 F: 1.83 (500 MHz, DMSO-d₆) δ 10.11 (s,1H), 8.34 (d, J = 7.7 Hz, 1H), 7.99-7.86 (m, 6H), 7.76 (d, J = 7.4 Hz,1H), 7.56 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 3.34 (br.s.,4H), 1.60 (br. s., 6H) 62

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-3-(pyrrolidin-1-yl)benzamide 411.2 E: 1.55 F: 1.80 ¹H NMR (500 MHz, DMSO-d₆) δ 12.81(s, 1H), 10.31 (s, 1H), 8.38-8.32 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H),7.94-7.85 (m, 2H), 7.76 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 8.5 Hz, 2H),7.36-7.27 (m, 1H), 7.19 (d, J = 7.4 Hz, 1H), 7.07 (s, 1H), 6.75 (dd, J =8.0, 1.7 Hz, 1H), 3.31 (br.s., 4H), 1.99 (t, J = 6.2 Hz, 4H) 63

4-(morpholin-4-yl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]benzamide 427.25 E: 1.42 F: 1.46 (500 MHz, DMSO-d₆) δ 12.81(br. s., 1H), 10.18 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 8.06-7.86 (m,6H), 7.80- 7.73 (m, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.8 Hz,2H), 3.82-3.71 (m, 4H), 3.29-3.22 (m, 4H) 64

4-(4-methylpiperazin-1- yl)-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]benzamide 440.25 E: 1.06 F: 1.18 ¹H NMR (500 MHz, DMSO-d₆) δ12.80 (s, 1H), 10.14 (s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 7.96 (d, J = 8.3Hz, 2H), 7.94-7.86 (m, 4H), 7.76 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.0Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 2.46 (br. s., 4H), 2.23 (s, 3H) 65

4-(1H-imidadzol-1-yl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]benzamide 408.2 E: 1.05 F: 1.29 ¹H NMR (500 MHz, DMSO-d₆) δ12.83 (s, 1H), 10.55 (s, 1H), 8.38 (s, 1H), 8.35 (d, J = 8.0 Hz, 1H),8.22 (s, 1H), 8.00-7.86 (m, 7H), 7.76 (d, J = 7.7 Hz, 1H), 7.71 (t, J =8.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.17 (s, 1H) 66

3-(dimethylamino)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]benzamide 385.1 E: 1.16 F: 1.64 (500 MHz, DMSO-d₆) δ 12.84(br. s., 1H), 10.35 (s, 1H), 8.40-8.31 (m, 1H), 8.00-7.86 (m, 4H), 7.76(d, J = 7.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.38-7.32 (m, 1H),7.28-7.23 (m, 2H), 6.95 (dd, J = 8.2, 2.2 Hz, 1H), 2.98 (s, 6H) 67

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]benzamide 342.2 E: 1.47F: 1.47 (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 10.48 (s, 1H), 8.35 (dd, J =7.7, 1.2 Hz, 1H), 8.04-7.96 (m, 4H), 7.95- 7.88 (m, 2H), 7.80-7.73 (m,1H), 7.65-7.52 (m, 5H)

Example 68: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenylisoindoline-2-carboxylate

Example 68A: 4-Bromophenyl isoindoline-2-carboxylate

To a solution of isoindoline (167 mg, 1.401 mmol) and DIEA (0.445 mL,2.55 mmol) in CH₂Cl₂ (3 mL), was added 4-bromophenyl carbonochloridate(300 mg, 1.274 mmol). The mixture was stirred at rt for 1 h, then wasquenched with water. The mixture was diluted with EtOAc (100 mL), thenwas washed with 1N HCl, sat Na₂CO₃ and brine, dried over Na₂SO₄, andconcentrated. The crude product was purified via flash chromatography toafford 310 mg (76%) of Example 68A. MS(ESI) m/z: 318.0 (M+H)⁺; ¹H NMR(500 MHz, CDCl₃) δ 7.53-7.48 (m, 2H), 7.36-7.29 (m, 4H), 7.13-7.07 (m,2H), 4.94 (s, 2H), 4.84 (s, 2H).

Example 68B: (4-((Isoindoline-2-carbonyl)oxy)phenyl)boronic acid

A mixture of Example 68A (100 mg, 0.314 mmol), bis(pinacolato)diboron(104 mg, 0.409 mmol), and potassium acetate (93 mg, 0.943 mmol) indioxane (3 mL) was degassed (3× vacuum/Ar). PdCl₂(dppf) CH₂Cl₂ adduct(6.90 mg, 9.43 μmol) was added, then the reaction mixture was degassedagain (3× vacuum/Ar), sealed in a vial and heated at 110° C. for 2 h.The reaction was concentrated and purified via preparative HPLC toafford 75 mg (84%) of Example 68B. MS(ESI) m/z: 284.1 (M+H)⁺; ¹H NMR(400 MHz, CD₃OD) δ 7.83-7.76 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.40-7.28(m, 4H), 7.24-7.10 (m, 2H), 4.95 (s, 2H), 4.78 (s, 2H).

Example 68

To 4-chlorophthalazin-1(2H)-one (18.24 mg, 0.101 mmol), Example 68B (26mg, 0.092 mmol) and potassium phosphate (48.7 mg, 0.230 mmol), wereadded dioxane (3 mL) and water (0.5 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (5.31 mg, 4.59 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The crudeproduct was purified by preparative HPLC to afford 9 mg (20%) of Example68. MS(ESI) m/z: 384.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s,1H), 8.45-8.29 (m, 1H), 7.92 (qd, J=7.3, 5.8 Hz, 2H), 7.75-7.69 (m, 1H),7.67-7.59 (m, 2H), 7.46-7.37 (m, 4H), 7.36-7.28 (m, 2H), 4.96 (s, 2H),4.76 (s, 2H); HPLC RT=1.77 min (Method E), 1.78 min (Method F).

Example 69: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl3-phenylpyrrolidine-1-carboxylate

Example 69A: 4-Bromophenyl 3-phenylpyrrolidine-1-carboxylate

To a mixture of 3-phenylpyrrolidine (141 mg, 0.956 mmol) and DIEA (0.223mL, 1.274 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (150 mg, 0.637 mmol). The mixture was stirred at rtfor 1 h. The reaction mixture was quenched with water and EtOAc (100 mL)was added. The organic phase was washed with 1N HCl, sat Na₂CO₃ andbrine, dried over Na₂SO₄, concentrated and purified flash chromatographyto afford 210 mg (95%) of Example 69A. MS(ESI) m/z: 345.9 (M+H)⁺; ¹H NMR(500 MHz, CDCl₃) δ 7.56-7.44 (m, 2H), 7.40-7.34 (m, 2H), 7.31-7.26 (m,3H), 7.09-6.99 (m, 2H), 4.12-3.94 (m, 1H), 3.89-3.73 (m, 1H), 3.64 (td,J=10.2, 6.7 Hz, 1H), 3.60-3.40 (m, 3H), 2.36 (ddtd, J=18.5, 12.4, 6.3,2.6 Hz, 1H), 2.18-2.01 (m, 1H).

Example 69B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl3-phenylpyrrolidine-1-carboxylate

To a mixture of Example 69A (210 mg, 0.607 mmol), bis(pinacolato)diboron(185 mg, 0.728 mmol), and potassium acetate (179 mg, 1.820 mmol) indioxane (5 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (13.31 mg, 0.018mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction mixture was dilutedwith water and extracted with EtOAc. The organic phase was concentrated,then purified via flash chromatography (EtOAc/hexanes) to afford 220 mg(92%) of Example 69B. MS(ESI) m/z: 394.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃)δ 7.86 (dd, J=7.8, 3.7 Hz, 2H), 7.42-7.35 (m, 2H), 7.33-7.26 (m, 3H),7.22 (t, J=7.0 Hz, 2H), 4.13-3.99 (m, 1H), 3.92-3.77 (m, 1H), 3.72-3.41(m, 3H), 2.38 (t, J=13.1 Hz, 1H), 2.19-2.07 (m, 1H), 1.37 (s, 12H).

Example 69

To 4-chlorophthalazin-1 (2H)-one (28 mg, 0.16 mmol), Example 69B (79 mg,0.20 mmol) and potassium phosphate (82 mg, 0.39 mmol), were addeddioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (9.0 mg, 7.8 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to afford 8.2 mg(10%) of the Example 69. MS(ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.85 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 7.99-7.86 (m, 2H),7.70 (d, J=7.4 Hz, 1H), 7.62 (dd, J=8.5, 3.9 Hz, 2H), 7.44-7.30 (m, 6H),7.29-7.19 (m, 1H), 4.13-3.97 (m, 1H), 3.97-3.76 (m, 1H), 3.72-3.59 (m,1H), 3.55-3.42 (m, 2H), 2.42-2.26 (m, 1H), 2.17-1.99 (m, 1H); HPLCRT=1.73 min (Method E), 1.74 min (Method F).

Example 70: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl5-methoxyisoindoline-2-carboxylate

Example 70A: 4-Bromophenyl 5-methoxyisoindoline-2-carboxylate

To a solution of 5-methoxyisoindoline (80 mg, 0.54 mmol) and DIEA (0.18mL, 1.02 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (120 mg, 0.51 mmol). The reaction mixture was stirredrt for 1 h, then was quenched with water. The mixture was diluted withEtOAc (100 mL). The organic phase was washed with 1N HCl, sat. Na₂CO₃and brine, dried over Na₂SO₄, and concentrated. The crude product waspurified via flash chromatography to afford 112 mg (63%) of Example 70A.MS(ESI) m/z: 348.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.55-7.45 (m, 2H),7.19 (dd, J=12.2, 8.4 Hz, 1H), 7.13-7.03 (m, 2H), 6.88 (dd, J=8.4, 2.3Hz, 1H), 6.82 (dd, J=10.5, 1.9 Hz, 1H), 4.87 (d, J=16.2 Hz, 2H), 4.78(d, J=17.1 Hz, 2H), 3.83 (s, 3H).

Example 70B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-methoxyisoindoline-2-carboxylate

To a mixture of Example 70A (112 mg, 0.322 mmol), bis(pinacolato)diboron(98 mg, 0.39 mmol), and potassium acetate (95 mg, 0.97 mmol) in dioxane(10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (7.1 mg, 9.7 μmol). Thereaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 2 h. The reaction was diluted with water andextracted with EtOAc. The organic phase was concentrated and the residuewas purified via flash chromatography to afford 100 mg (79%) of Example70B. MS(ESI) m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J=8.3Hz, 2H), 7.25-7.15 (m, 3H), 6.92-6.80 (m, 2H), 4.89 (d, J=16.5 Hz, 2H),4.79 (d, J=18.2 Hz, 2H), 3.83 (s, 3H), 1.44-1.32 (m, 12H).

Example 70

To 4-chlorophthalazin-1(2H)-one (13 mg, 0.072 mmol), Example 70B (29.9mg, 0.076 mmol) and potassium phosphate (38.2 mg, 0.180 mmol), wereadded dioxane (3 mL) and water (0.33 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (4.2 mg, 3.6 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated, then was purified via preparative HPLC toafford 9 mg (23%) of Example 70. MS(ESI) m/z: 414.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.86 (s, 1H), 8.35 (dd, J=7.6, 1.2 Hz, 1H), 7.98-7.88(m, 2H), 7.76-7.70 (m, 1H), 7.68-7.61 (m, J=8.5 Hz, 2H), 7.43-7.36 (m,J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 6.99 (br. s., 1H), 6.91 (d, J=8.3Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H),3.81-3.72 (m, 3H); HPLC RT=9.48 min (Method A), 8.98 min (Method B).

Example 71: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl5-fluoroisoindoline-2-carboxylate

Example 71A: 4-Bromophenyl 5-fluoroisoindoline-2-carboxylate

To a mixture of 5-fluoroisoindoline (141 mg, 1.03 mmol) and DIEA (0.326mL, 1.87 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (220 mg, 0.934 mmol). The mixture was stirred at rtfor 1 h, then was quenched with water. The mixture was diluted withEtOAc (100 mL), then was washed with 1N HCl, sat Na₂CO₃ and brine, driedover Na₂SO₄, and concentrated. The crude product was purified via flashchromatography (EtOAc/hexanes) to afford 190 mg (61%) of Example 71A.MS(ESI) m/z: 414.1 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ 7.56-7.46 (m, 2H),7.34-7.21 (m, 1H), 7.16-7.07 (m, 2H), 7.05-6.97 (m, 2H), 4.92 (d, J=14.0Hz, 2H), 4.82 (d, J=14.0 Hz, 2H).

Example 71B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-fluoroisoindoline-2-carboxylate

To a mixture of Example 71A (182 mg, 0.541 mmol), bis(pinacolato)diboron(165 mg, 0.65 mmol), and potassium acetate (159 mg, 1.62 mmol) indioxane (4 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (11.9 mg, 0.016mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction mixture was partitionedbetween EtOAc and H₂O. The organic phase was concentrated and theresidue was purified via flash chromatography to afford 150 mg (72%) ofExample 71B. MS(ESI) m/z: 384.2 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ7.88-7.83 (m, 2H), 7.28-7.19 (m, 3H), 7.09-6.95 (m, 2H), 4.93 (d, J=14.3Hz, 2H), 4.82 (d, J=14.0 Hz, 2H), 1.43-1.34 (m, 12H).

Example 71

To 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol), Example 71B (44.6mg, 0.116 mmol) and potassium phosphate (58.8 mg, 0.277 mmol), wereadded dioxane (3 mL) and water (0.33 mL). The mixture was degassed(evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (6.4 mg, 5.5 μmol) wasadded, then the mixture was degassed (2×). The reaction vial was sealedand heated in a microwave reactor at 150° C. for 25 min. The reactionmixture was concentrated and the residue purified via preparative HPLCto afford 5 mg (8%) of Example 71. MS(ESI) m/z: 402.1 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ 12.86 (s, 1H), 8.39-8.32 (m, 1H), 7.95-7.89 (m,2H), 7.75-7.69 (m, 1H), 7.66-7.60 (m, 2H), 7.44-7.35 (m, 4H), 7.29-7.15(m, 4H), 4.94 (d, J=17.3 Hz, 2H), 4.74 (d, J=17.1 Hz, 2H); HPLC RT=9.62min (Method A), 9.15 min (Method B).

Example 72: 4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2 TFA

Example 72A: 4-Bromophenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate, 2 TFA

To a solution of Intermediate 2 (196 mg, 0.849 mmol) and DIEA (0.297 mL,1.70 mmol) in CH₂Cl₂ (3 mL) at 0° C., was added 4-bromophenylcarbonochloridate (200 mg, 0.849 mmol). The mixture was stirred at rtfor 1 h. The reaction mixture was quenched with water and diluted withEtOAc (100 mL). The organic phase was washed with 1N HCl, sat Na₂CO₃ andbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography, followed by preparative HPLC to afford280 mg (50%) of Example 72A. MS(ESI) m/z: 430.1 (M+H)⁺; ¹H NMR (500 MHz,CD₃OD) δ 7.60-7.51 (m, 2H), 7.49-7.38 (m, 3H), 7.21-7.10 (m, 2H), 4.96(s, 2H), 4.79 (s, 2H), 4.15 (s, 2H), 3.49 (br. s., 4H), 3.30-3.19 (m,4H), 2.94 (s, 3H).

Example 72B: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

To a mixture of Example 72A (70 mg, 0.106 mmol), bis(pinacolato)diboron(32.4 mg, 0.128 mmol), and potassium acetate (31.3 mg, 0.319 mmol) indioxane (10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (2.3 mg, 3.2 μmol).The reaction mixture was degassed (3× vacuum/Ar), sealed in a vial andheated at 110° C. for 2 h. The reaction was quenched with water, thenextracted with EtOAc. The organic phase was concentrated to afford 80 mgof Example 72B, which was used as is in the following step withoutfurther purification. MS(ESI) m/z: 478.4 (M+H)⁺.

Example 72

To a vial containing 4-chlorophthalazin-1(2H)-one (22 mg, 0.12 mmol),Example 72B (80 mg, 0.106 mmol) and potassium phosphate (64.6 mg, 0.305mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture wasdegassed (evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (7.0 mg, 6.1μmol) was added, then the mixture was degassed (2×). The reaction vialwas sealed and heated in a microwave reactor at 150° C. for 25 min. Thereaction mixture was concentrated and purified via preparative HPLC toafford 22 mg (25%) of Example 72. MS(ESI) m/z: 496.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.86 (s, 1H), 8.43-8.31 (m, 1H), 8.02-7.86 (m, 2H),7.71 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.47-7.34 (m, 4H), 7.30(d, J=7.4 Hz, 1H), 4.95 (s, 2H), 4.76 (br. s., 2H), 3.65 (br. s., 2H),2.99 (br. s., 4H), 2.77 (br. s., 3H), 2.36 (br. s., 2H); HPLC RT=4.32min (Method A), 5.17 min (Method B).

Example 73: 4-(4-((5-Phenyloxazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

Example 73A: N-(4-Bromophenyl)-5-phenyloxazol-2-amine

To a solution of 2-azido-1-phenylethanone (Angew. Chem. Int. Ed.,46:4489-4491 (2007)) (126 mg, 0.782 mmol) and1-bromo-4-isothiocyanatobenzene (167 mg, 0.782 mmol) in dioxane (4 mL)at 80° C., was added triphenylphosphine (205 mg, 0.782 mmol). Themixture was stirred at 85° C. for 30 min, then was cooled to rt. Thereaction mixture was concentrated. The solid was recrystallized from hotCH₃C₁ (˜5 mL). The precipitate was suspended in EtOAc (˜3 mL), filteredand collected to afford 134 mg (54%) of Example 73A as a white solid.MS(ESI) m/z: 315.0 (M+H)⁺; ¹H NMR (400 MHz, CD₃OD) δ 7.62-7.57 (m, 2H),7.51-7.46 (m, 2H), 7.46-7.41 (m, 2H), 7.39 (t, J=7.7 Hz, 2H), 7.26 (dt,J=7.4, 1.3 Hz, 1H), 7.24 (s, 1H).

Example 73B:5-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxazol-2-amine

To a vial containing Example 73A (136 mg, 0.432 mmol),bis(pinacolato)diboron (164 mg, 0.647 mmol) and potassium acetate (127mg, 1.30 mmol), was added dioxane (2 mL). The mixture was degassed(evacuated and flushed with Ar (3×)). PdCl₂(dppf) CH₂Cl₂ adduct (17.6mg, 0.022 mmol) was added, then the mixture was degassed (2×), then wassealed. The mixture was stirred at 110° C. for 2 h. The reaction mixturewas diluted with EtOAc. The organic phase was washed with H₂O and brine,dried (Na₂SO₄) and concentrated. The crude product was purified by flashchromatography (gradient from 0 to 50% ethyl acetate/hexanes) to afford122 mg (78%) of Example 73B as a white solid. MS(ESI) m/z: 363.1 (M+H)⁺;¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.8 Hz, 2H), 7.55 (dd, J=8.3, 1.2Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.42-7.36 (m, 2H),7.29-7.23 (m, 1H), 7.18 (s, 1H), 1.35 (s, 12H).

Example 73

To 4-chlorophthalazin-1(2H)-one (36.7 mg, 0.203 mmol), Example 73B (67mg, 0.185 mmol) and potassium phosphate (98 mg, 0.46 mmol) in dioxane (3mL) and water (0.5 mL), was added Pd(PPh₃)₄ (10.7 mg, 9.25 μmol). Themixture was degassed (3×), then the reaction vial was sealed and heatedin a microwave reactor at 150° C. for 25 min. The crude product waspurified by preparative HPLC to afford 9.7 mg (11%) of Example 73.MS(ESI) m/z: 381.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.78 (s, 1H),10.60 (s, 1H), 8.40-8.30 (m, 1H), 7.96-7.87 (m, 2H), 7.84-7.73 (m, 3H),7.62 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (t,J=7.7 Hz, 2H), 7.33-7.24 (m, 1H); HPLC RT=8.99 min (Method A), 8.46 min(Method B).

Example 74: 4-(4-((4-Phenylthiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

Example 74A: N-(4-Bromophenyl)-4-phenylthiazol-2-amine

2-Bromo-1-phenylethanone (105 mg, 0.528 mmol) and1-(4-bromophenyl)thiourea (122 mg, 0.528 mmol) were mixed in glycerol (5mL) and stirred at 90° C. for 2 h. The reaction mixture was partitionedbetween EtOAc and water. The organic phase was concentrated and purifiedvia flash chromatography (EtOAc/hexanes) to afford 165 mg (94%) ofExample 74A. MS(ESI) m/z: 331.0 (M+H)⁺; ¹H NMR (500 MHz, CDCl₃) δ7.87-7.82 (m, 2H), 7.44-7.38 (m, 4H), 7.36-7.31 (m, 1H), 7.29-7.22 (m,2H), 6.84 (s, 1H).

Example 74B:4-Phenyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiazol-2-amine

To a mixture of Example 74A (160 mg, 0.483 mmol), bis(pinacolato)diboron(147 mg, 0.580 mmol), and potassium acetate (142 mg, 1.45 mmol) indioxane (10 mL), was added PdCl₂(dppf) CH₂Cl₂ adduct (10.6 mg, 0.014mmol). The reaction mixture was degassed (3× vacuum/Ar), sealed in avial and heated at 110° C. for 2 h. The reaction was diluted with waterand extracted with EtOAc. The organic phase was concentrated and theproduct purified via flash chromatography to afford 130 mg (71%) ofExample 74B. MS(ESI) m/z: 379.0 (M+H)⁺.

Example 74

To 4-chlorophthalazin-1(2H)-one (18 mg, 0.10 mmol), Example 74B (45.2mg, 0.120 mmol) and potassium phosphate (53 mg, 0.25 mmol), were addeddioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuatedand flushed with Ar (5×)). Pd(PPh₃)₄ (5.8 mg, 5.0 μmol) was added, thenthe mixture was degassed (2×). The reaction vial was sealed and heatedin a microwave reactor at 150° C. for 35 min. The reaction mixture wasconcentrated, then was purified by preparative HPLC to afford 2.0 mg(3.9%) of Example 74. MS(ESI) m/z: 397.0 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.78 (s, 1H), 10.53 (s, 1H), 8.39-8.31 (m, 1H), 8.01-7.86(m, 6H), 7.81 (d, J=7.4 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.48-7.38 (m,3H), 7.37-7.30 (m, 1H); HPLC RT=1.85 min (Method E), 1.90 min (MethodF).

Example 75: 4-(4-(Benzo[d]oxazol-2-ylamino)phenyl)phthalazin-1(2H)-one

Intermediate 3 (35 mg, 0.100 mmol), 2-chlorobenzo[d]oxazole (0.015 mL,0.130 mmol), and DIEA (0.087 mL, 0.498 mmol) were dissolved in NMP (1mL) and the reaction mixture was heated in a capped vial at 150° C. for18 h. The reaction mixture was purified by preparative HPLC to afford5.0 mg (14%) of Example 75. MS(ESI) m/z: 355.05 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.83 (s, 1H), 10.90 (br. s., 1H), 8.39-8.30 (m, 1H), 7.94(d, J=8.4 Hz, 2H), 7.93-7.87 (m, 2H), 7.80-7.76 (m, 1H), 7.63 (d, J=8.4Hz, 2H), 7.51 (dd, J=16.6, 7.7 Hz, 2H), 7.28-7.22 (m, 1H), 7.19-7.14 (m,1H); HPLC RT=1.58 min (Method E), 1.64 min (Method F).

Example 76:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide

To 4-chlorophthalazin-1(2H)-one (29 mg, 0.16 mmol), Intermediate 10 andpotassium phosphate (85 mg, 0.40 mmol), were added dioxane (3 mL) andwater (0.33 mL). The mixture was degassed (evacuated and flushed with Ar(5×)). Pd(PPh₃)₄ (9.28 mg, 8.03 μmol) was added, then the mixture wasdegassed (2×). The reaction vial was sealed and heated in a microwavereactor at 150° C. for 30 min. The reaction mixture was concentrated andpurified via preparative HPLC to afford 6.1 mg (9.4%) of Example 76.MS(ESI) m/z: 383.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H),8.74 (s, 1H), 8.34 (dd, J=7.7, 1.2 Hz, 1H), 8.00-7.85 (m, 3H), 7.76 (d,J=8.9 Hz, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.14 (t,J=7.7 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 4.18 (t, J=8.7 Hz, 2H), 3.20 (t,J=8.7 Hz, 2H); HPLC RT=1.65 min (Method E), 1.66 min (Method F).

Example 77:N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 6 (28 mg, 0.125 mmol) and Intermediate 10 (54.6 mg,0.150 mmol) afforded 7.5 mg (16%) of Example 77. MS(ESI) m/z: 382.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.41 (br. s., 1H), 8.63 (s, 1H),8.30 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.75-7.66 (m, 3H),7.59-7.51 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 7.21 (d, J=7.4 Hz, 1H), 7.13(t, J=7.7 Hz, 1H), 7.07 (s, 1H), 6.91 (t, J=7.3 Hz, 1H), 4.17 (t, J=8.5Hz, 2H), 3.20 (t, J=8.3 Hz, 2H); HPLC RT=1.77 min (Method E), 1.73 min(Method F).

Example 78:4-{4-[(Quinazolin-2-yl)amino]phenyl}-1,2-dihydrophthalazin-1-one, TFA

According to the procedure for the preparation of Example 75,Intermediate 3 (35 mg, 0.100 mmol) was reacted with 2-chloroquinazolineat 150° C. for 40 h to afford 4.1 mg (8.6%) of Example 78. MS(ESI) m/z:366.2 (M+H)⁺; ¹H-NMR: (500 MHz, DMSO-d₆) δ ppm 12.78 (s, 1H), 10.14 (s,1H), 9.37 (s, 1H), 8.38-8.31 (m, 1H), 8.19 (d, J=8.5 Hz, 2H), 7.96 (d,J=7.7 Hz, 1H), 7.93-7.87 (m, 2H), 7.84-7.78 (m, 2H), 7.72 (d, J=8.3 Hz,1H), 7.57 (d, J=8.5 Hz, 2H), 7.42 (t, J=7.3 Hz, 1H); HPLC RT=1.45 min(Method E), 1.70 min (Method F).

Example 79: 4-(4-(Quinazolin-2-ylamino)phenyl)phthalazin-1(2H)-one, TFA

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (25 mg, 0.14 mmol) and Intermediate 12(60.0 mg, 0.152 mmol) afforded 2.5 mg (4.3%) of Example 79. MS(ESI) m/z:413.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (br. s., 1H), 8.72 (s,1H), 8.38-8.30 (m, 1H), 8.01-7.86 (m, 2H), 7.76 (d, J=8.5 Hz, 3H),7.60-7.49 (m, 3H), 7.09 (d, J=8.3 Hz, 1H), 6.49 (dd, J=8.3, 2.5 Hz, 1H),4.19 (t, J=8.7 Hz, 2H), 3.72 (s, 3H), 3.12 (t, J=8.5 Hz, 2H); HPLCRT=1.67 min (Method E), 1.67 min (Method F).

Example 80:6-Methoxy-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 6 (29 mg, 0.129 mmol) and Intermediate 12 (61.2 mg,0.155 mmol) afforded 5.9 mg (11%) of Example 80. MS(ESI) m/z: 412.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (br. s., 1H), 8.63 (s, 1H),8.30 (d, J=8.0 Hz, 1H), 7.75-7.66 (m, 3H), 7.60-7.51 (m, 3H), 7.35 (d,J=8.5 Hz, 2H), 7.11-7.03 (m, 2H), 6.48 (dd, J=8.1, 2.3 Hz, 1H), 4.18 (t,J=8.5 Hz, 2H), 3.72 (s, 3H), 3.11 (t, J=8.5 Hz, 2H); HPLC RT=1.47 min(Method E), 1.48 min (Method F).

Example 81:(R)—N-(2,3-Dihydro-1H-inden-1-yl)-2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetamide

According to the procedure for the preparation of Example 3, coupling ofIntermediate 1 (25 mg, 0.089 mmol) with (R)-2,3-dihydro-1H-inden-1-amine(14.3 mg, 0.107 mmol) afforded 13.7 mg (38%) of Example 81. MS(ESI) m/z:396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.53 (d, J=8.3Hz, 1H), 8.38-8.32 (m, 1H), 7.94-7.85 (m, 2H), 7.74-7.68 (m, 1H),7.58-7.52 (m, 2H), 7.50-7.45 (m, 2H), 7.29-7.24 (m, 1H), 7.24-7.14 (m,3H), 5.29 (q, J=7.8 Hz, 1H), 3.64-3.54 (m, 2H), 2.99-2.90 (m, 1H),2.86-2.76 (m, 1H), 2.46-2.37 (m, 1H), 1.81 (dq, J=12.7, 8.4 Hz, 1H);HPLC RT=1.58 min (Method E), 1.60 min (Method F).

Example 82:(S)—N-(2,3-Dihydro-1H-inden-1-yl)-2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetamide

According to the procedure for the preparation of Example 3, coupling ofIntermediate 1 (25 mg, 0.089 mmol) with (S)-2,3-dihydro-1H-inden-1-amine(14.3 mg, 0.107 mmol) afforded 19.7 mg (56%) of Example 82. MS(ESI) m/z:396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.53 (d, J=8.3Hz, 1H), 8.38-8.31 (m, 1H), 7.94-7.86 (m, 2H), 7.75-7.68 (m, 1H),7.58-7.52 (m, 2H), 7.50-7.45 (m, 2H), 7.28-7.24 (m, 1H), 7.24-7.14 (m,3H), 5.29 (q, J=7.9 Hz, 1H), 3.65-3.54 (m, 2H), 2.99-2.91 (m, 1H), 2.81(dt, J=16.0, 8.3 Hz, 1H), 2.46-2.37 (m, 1H), 1.81 (dq, J=12.5, 8.4 Hz,1H); HPLC RT=1.63 min (Method E), 1.63 min (Method F).

Example 83:4-(4-(2-(6-(Benzyloxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 3, coupling ofIntermediate 1 (56 mg, 0.20 mmol) with 6-(benzyloxy)indoline (71.2 mg,0.21 mmol) afforded 38 mg (38%) of Example 83. MS(ESI) m/z: 488.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.40-8.30 (m, 1H),7.99-7.81 (m, 3H), 7.76-7.69 (m, 1H), 7.60-7.53 (m, 2H), 7.50-7.44 (m,J=8.0 Hz, 2H), 7.44-7.40 (m, 2H), 7.39-7.34 (m, 2H), 7.34-7.26 (m, 1H),7.12 (d, J=8.3 Hz, 1H), 6.66 (dd, J=8.1, 2.3 Hz, 1H), 5.05 (s, 2H), 4.24(t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.10 (t, J=8.3 Hz, 2H); HPLC RT=10.56min (Method A), 9.34 min (Method B).

Example 84

Intermediate 13 (50 mg, 0.12 mmol), benzo[d]thiazol-2-amine (17.8 mg,0.119 mmol),di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine(7.6 mg, 0.016 mmol), Pd₂(dba)₃ (3.3 mg, 3.6 μmol) and K₂CO₃ (23 mg,0.17 mmol) were added in a pressure vial. The reaction mixture wasdegassed (3× vacuum/Ar), and then tBuOH (1 mL) and AcOH (1 drop) wereadded. The reaction mixture was degassed again, capped, and stirred at110° C. for 3 h. The reaction mixture was diluted with MeOH/DMSO,filtered and purified by preparative HPLC to afford4-(4-(benzo[d]thiazol-2-ylamino)phenyl)-2-(4-methoxybenzyl)phthalazin-1(2H)-one(45.9 mg, 79% yield) as a white solid. MS(ESI) m/z: 491.1 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.77 (br. s., 1H), 8.38 (br. s., 1H), 7.99 (d,J=7.9 Hz, 2H), 7.92 (d, J=3.3 Hz, 2H), 7.85 (d, J=7.7 Hz, 2H), 7.69-7.56(m, 3H), 7.35 (d, J=6.2 Hz, 3H), 7.19 (t, J=7.0 Hz, 1H), 6.90 (d, J=7.9Hz, 2H), 5.32 (br. s., 2H), 3.71 (s, 3H). The residue was dissolved inTFA (3 mL) and was sealed vial and was heated in a microwave reactor at150° C. for 30 min. The reaction mixture was evaporated and was purifiedby preparative HPLC to afford 2.3 mg (6%) of Example 84. MS(ESI) m/z:371.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.80 (s, 1H), 10.72 (s,1H), 8.35 (d, J=7.4 Hz, 1H), 7.98 (d, J=8.5 Hz, 2H), 7.94-7.89 (m, 2H),7.85 (d, J=8.0 Hz, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H),7.61 (d, J=8.5 Hz, 2H), 7.36 (t, J=7.7 Hz, 1H), 7.19 (t, J=7.6 Hz, 1H);HPLC RT=1.68 min (Method E), 1.84 min (Method F).

Example 85: 4-(4-(Phthalazin-1-ylamino)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 84,Intermediate 13 (50 mg, 0.12 mmol) and 1-chlorophthalazine (25.3 mg,0.154 mmol) afforded after coupling and deprotection 6.6 mg (40%) ofExample 85. MS(ESI) m/z: 366.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.81 (s, 1H), 9.39 (s, 1H), 9.20 (s, 1H), 8.65 (d, J=8.0 Hz, 1H), 8.36(d, J=7.7 Hz, 1H), 8.16 (d, J=8.3 Hz, 2H), 8.09-8.05 (m, 1H), 8.03 (d,J=7.7 Hz, 1H), 8.02-7.97 (m, 1H), 7.96-7.88 (m, 2H), 7.84 (d, J=7.7 Hz,1H), 7.61 (d, J=8.5 Hz, 2H); HPLC RT=1.07 min (Method E), 1.40 min(Method F).

Example 86:4-{4-[(5-Methyl-1,3-benzoxazol-2-yl)amino]phenyl}-1,2-dihydrophthalazin-1-one

According to the procedure for the preparation of Example 76, couplingof 2-chloro-5-methylbenzo[d]oxazole (25.05 mg, 0.149 mmol) andIntermediate 12 (35 mg, 0.10 mmol) afforded 6.8 mg (18%) of Example 86.MS(ESI) m/z: 469.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.80 (br. s.,1H), 8.34 (d, J=7.7 Hz, 1H), 7.97-7.84 (m, 4H), 7.78 (d, J=7.7 Hz, 1H),7.61 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 1H), 7.29 (s, 1H), 6.96 (d,J=8.3 Hz, 1H), 2.38 (s, 3H); HPLC RT=1.75 min (Method E), 1.81 min(Method F).

Example 87:4-(4-((5-Phenyl-1,3,4-thiadiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

Intermediate 14 (50 mg, 0.14 mmol) and2-chloro-5-phenyl-1,3,4-thiadiazole (33 mg, 0.17 mmol) were dissolved indry THF (2 mL). Then, LiHMDS (1 M in THF) (0.364 mL, 0.364 mmol) wasadded dropwise to the stirred reaction mixture. The reaction mixture wasstirred at 50° C. for 1 h. The reaction mixture was cooled to rt,quenched with MeOH (1 mL), and concentrated under reduced pressure. Theresidue was redissolved in TFA (3 mL), and stirred at 150° C. for 15 minunder microwave irradiation. TFA was evaporated, then the residue waspurified by prep HPLC to afford 14.1 mg (25%) of Example 87. MS(ESI)m/z: 498.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.80 (s, 1H), 10.79(br. s., 1H), 8.35 (d, J=7.4 Hz, 1H), 7.98-7.87 (m, 4H), 7.85 (d, J=8.0Hz, 2H), 7.78 (d, J=7.7 Hz, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.56-7.48 (m,3H); HPLC RT=1.67 min (Method E), 1.68 min (Method F).

Example 88:4-(4-((5-Phenylthiazol-2-yl)amino)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 87, couplingof Intermediate 14 (40 mg, 0.112 mmol) and 2-chloro-5-phenylthiazole(26.3 mg, 0.134 mmol) afforded after TFA deprotection and HPLCpurification 1.3 mg (3%) on Example 88. MS(ESI) m/z: 397.2 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ ppm 12.78 (br. s., 1H), 10.59 (br. s., 1H),8.34 (d, J=7.2 Hz, 1H), 7.96-7.87 (m, 2H), 7.85-7.76 (m, 3H), 7.74 (s,1H), 7.56 (d, J=7.7 Hz, 4H), 7.40 (t, J=7.2 Hz, 2H), 7.31-7.24 (m, 1H);HPLC RT=1.74 min (Method E), 1.95 min (Method F).

The following Examples in Table 3 were made by using the same procedureas shown in Example 45. Intermediate 3 was coupled with the appropriatecarboxylic acid. Various coupling reagents could be used other than theone described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.

TABLE 3 LC HPLC MS Method, Ex- (M + RT ample R Name H)⁺ (min.) ¹H NMR 89

N-[4-(4-oxo-3,4 dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]pyridine-2-carboxamide 382.1 A: 5.21 B: 5.58 ¹H NMR (500 MHz, DMSO-d₆) d12.82 (s, 1H), 10.58 (s, 1H), 8.69 (d, J = 6.9 Hz, 1H), 8.63 (s, 1H),8.35 (dd, J = 7.8, 1.5 Hz, 1H), 8.14-8.03 (m, J = 8.5 Hz, 2H), 7.91(quind, J = 7.6, 1.4 Hz, 2H), 7.81-7.74 (m, 1H), 7.71 (d, J = 9.1 Hz,1H), 7.64-7.57 (m, J = 8.5 Hz, 2H), 7.49-7.42 (m, 1H), 7.10 (t, J = 6.7Hz, 1H) 90

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 395.1 E: 1.77 F: 1.79 ¹H NMR (500 MHz, DMSO-d₆) d 12.82 (br.s., 1H), 10.54 (br. s., 1H), 8.39-8.32 (m, 1H), 7.99 (d, J = 8.5 Hz,2H), 7.97-7.85 (m, 2H), 7.77 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.0 Hz,1H), 7.63-7.54 (m, 3H), 7.38 (s, 1H), 7.34-7.30 (m, 1H), 7.19-7.10 (m,1H), 4.11-4.00 (m, 3H) 91

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2,3-dihydro-1H-indene-1- carboxamide 382.1 E: 1.68 F: 1.70 ¹H NMR (500 MHz, DMSO-d₆)d 12.79 (s, 1H), 10.47 (s, 1H), 8.37-8.31 (m, 1H), 7.94-7.85 (m, 2H),7.83 (d, J = 8.5 Hz, 2H), 7.76-7.71 (m, 1H), 7.55 (d, J = 8.5 Hz, 2H),7.34 (d, J = 6.9 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.24- 7.14 (m, 2H),4.17 (t, J = 7.4 Hz, 1H), 3.13-3.03 (m, 1H), 2.97-2.87 (m, 1H),2.44-2.24 (m, 2H) 92

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide 409.1 E: 1.33 F: 1.33 ¹H NMR (500 MHz, DMSO-d₆) d12.82 (s, 1H), 10.56 (s, 1H), 9.46 (s, 1H), 8.39-8.28 (m, 2H), 8.24-8.18(m, J = 8.5 Hz, 2H), 8.11-8.03 (m, J = 8.5 Hz, 2H), 8.03-7.84 (m, 4H),7.77 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H) 93

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2,1- benzoxazole-3-carboxamide 383.0 A: 8.48 B: 7.27 ¹H NMR (500 MHz, DMSO-d₆) d12.88-12.80 (m, 1H), 11.33 (br. s., 1H), 8.35 (d, J = 7.2 Hz, 1H),8.14-8.02 (m, 3H), 7.92 (t, J = 7.0 Hz, 2H), 7.84 (d, J = 6.6 Hz, 1H),7.76 (d, J = 6.3 Hz, 1H), 7.64 (d, J = 5.8 Hz, 2H), 7.56 (t, J = 6.7 Hz,1H), 7.36 (t, J = 6.2 Hz, 1H) 94

6-(dimethylamino)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-2- carboxamide 424.2 E: 1.23 F: 1.74 ¹H NMR (500MHz, DMSO-d₆) d 12.81 (s, 1H), 11.29 (s, 1H), 10.20 (s, 1H), 8.35 (d, J= 7.4 Hz, 1H), 8.05-7.85 (m, 5H), 7.78 (d, J = 8.0 Hz, 1H), 7.59 (d, J =8.3 Hz, 2H), 7.49 (d, J = 9.1 Hz, 1H), 7.34 (s, 1H), 6.76 (dd, J = 8.8,1.9 Hz, 1H), 6.65 (s, 1H), 2.93 (s, 6H) 95

2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide 396.1 E: 1.12 F: 1.37 ¹H NMR (500 MHz, DMSO-d₆) d12.82 (s, 1H), 10.11 (s, 1H), 8.96 (d, J = 6.9 Hz, 1H), 8.35 (d, J = 7.4Hz, 1H), 7.95- 7.86 (m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.66-7.58 (m,3H), 7.47-7.41 (m, 1H), 7.08 (t, J = 6.7 Hz, 1H), 2.68 (s, 3H) 96

5-chloro-1-methyl-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-2- carboxamide 429.1 E: 2.02 F: 2.02 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.61 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.04-7.87 (m, 4H), 7.81 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.65 (d, J =8.8 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.37-7.28 (m, 2H), 4.04 (s, 3H)97

5,5-dimethyl-4-oxo-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-4,5,6,7- tetrahydro-1H-indole-3- carboxamide 427.2 ¹H NMR(500 MHz, DMSO-d₆) Shift 12.82 (d, J = 5.8 Hz, 2H), 12.11 (br. s., 1H),8.34 (d, J = 6.1 Hz, 1H), 7.97-7.50 (m, 8H), 2.89 (d, J = 4.3 Hz, 2H),1.99 (br. s., 2H), 1.21 (br. s., 6H) 98

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole-3-carboxamide 396.2 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83 (s, 1H), 10.58(s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.10 (d, J= 8.5 Hz, 2H), 7.98-7.86 (m, 2H), 7.79 (dd, J = 18.6, 8.2 Hz, 2H), 7.59(d, J = 8.2 Hz, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H),4.23 (s, 3H) 99

1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole-3-carboxamide 472.2 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83 (s, 1H), 10.61(s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, 1H), 8.10 (d, J= 8.2 Hz, 2H), 7.98-7.87 (m, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.77 (d, J =7.0 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H),7.41-7.22 (m, 6H), 5.86 (s, 2H) 100

5-ethoxy-2-methyl-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1-benzofuran- 3-carboxamide 440.2 ¹H NMR (500 MHz, DMSO-d₆)Shift 12.83 (s, 1H), 10.29 (s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 7.97-7.84(m, 4H), 7.77 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 2H), 7.50 (d, J= 8.9 Hz, 1H), 7.20 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 4.07 (q, J = 7.0Hz, 2H), 2.67 (s, 3H), 1.35 (t, J = 6.7 Hz, 3H) 101

5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 395.1 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83 (s, 1H), 11.68(br. s., 1H), 10.38 (s, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 7.6Hz, 2H), 7.96-7.84 (m, 3H), 7.78 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 7.3Hz, 2H), 7.47 (s, 1H), 7.42-7.33 (m, 2H), 7.07 (d, J = 8.5 Hz, 1H), 2.39(s, 3H) 102

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]pyrimidine-2- carboxamide 441.2 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83(s, 1H), 10.73 (s, 1H), 9.20 (d, J = 6.7 Hz, 1H), 8.74-8.66 (m, 1H),8.35 (d, J = 7.6 Hz, 1H), 8.07 (d, J = 8.5 Hz, 2H), 7.97-7.87 (m, 2H),7.76 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 7.25(dd, J = 7.0, 4.0 Hz, 1H) 103

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide 382.0 A: 7.05 B: 6.25 ¹H NMR (500 MHz, DMSO-d₆) δ12.81 (s, 1H), 10.15 (s, 1H), 8.91-8.81 (m, 2H), 8.43-8.27 (m, 2H),8.05-7.87 (m, 4H), 7.78 (d, J = 7.5 Hz, 1H), 7.65-7.53 (m, 3H), 7.14 (t,J = 6.8 Hz, 1H), 6.59-6.45 (m, 1H) 104

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]pyridine-3-carboxamide ¹H NMR (500 MHz, DMSO-d₆) Shift 12.84 (s, 1H),10.42 (s, 1H), 9.50 (d, J = 6.7 Hz, 1H), 8.64 (s, 1H), 8.35 (d, J = 7.6Hz, 1H), 7.98-7.84 (m, 4H), 7.78 (t, J = 7.5 Hz, 2H), 7.61 (d, J = 8.5Hz, 2H), 7.57-7.50 (m, 1H), 7.21 (t, J = 6.7 Hz, 1H) 105

5-(benzyloxy)-2-methyl- N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1-benzofuran- 3-carboxamide 502.1 C: 3.04 D: 4.07 ¹H NMR (500MHz, DMSO-d₆) Shift 12.84 (s, 1H), 10.29 (s, 1H), 8.35 (d, J = 7.9 Hz,1H), 7.97-7.84 (m, 4H), 7.76 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.2 Hz,2H), 7.52 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 7.6 Hz, 2H), 7.39 (t, J =7.3 Hz, 2H), 7.35-7.27 (m, 2H), 7.01 (d, J = 8.9 Hz, 1H), 5.15 (s, 2H),2.66 (s, 3H) 106

5-hydroxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-yl)phenyl]-2,3-dihydro-1- benzofuran-2- carboxamide 400.2 C: 1.90 D:2.96 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.81 (s, 1H), 10.29 (s, 1H), 8.91(br. s., 1H), 8.51-8.25 (m, 1H), 7.94-7.80 (m, 4H), 7.75-7.65 (m, 1H),7.55 (d, J = 8.5 Hz, 2H), 6.75- 6.62 (m, 2H), 6.53 (d, J = 6.1 Hz, 1H),5.28 (dd, J = 9.8, 6.7 Hz, 1H), 3.55-3.41 (m, 1H) 107

1-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 409.2 C: 2.81 D: 3.95 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83(s, 1H), 10.54 (s, 1H), 8.35 (d, J = 7.0 Hz, 1H), 7.99 (d, J = 8.5 Hz,2H), 7.93-7.87 (m, 2H), 7.80-7.67 (m, 2H), 7.65-7.53 (m, 3H), 7.38 (s,1H), 7.32 (t, J = 7.8 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 4.62 (d, J =7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H) 108

4-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5-(propan-2-yl)-3H,4H-pyrrolo[2,1-f] [1,2,4]triazine-6- carboxamide 441.2 C: 2.08 D:3.31 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.82 (s, 1H), 11.64 (br. s., 1H),10.21 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.10 (s, 1H), 7.93-7.84 (m,5H), 7.76 (d, J = 7.3 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 4.13-4.00 (m,1H), 1.36 (d, J = 7.0 Hz, 6H) 109

4-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-4,5,6,7-tetrahydro-1H-indazole- 3-carboxamide 400.3 C: 2.01 D: 3.40 ¹H NMR (500MHz, DMSO-d₆) Shift 12.84 (s, 1H), 12.60 (br. s., 1H), 8.34 (d, J = 6.7Hz, 1H), 7.96-7.86 (m, 4H), 7.77 (d, J = 7.6 Hz, 1H), 7.65 (d, J = 7.3Hz, 2H), 2.92 (br. s., 2H), 2.67 (br. s., 2H), 2.16-2.07 (m, 2H) 110

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrazolo[3,4-b]pyridine- 3-carboxamide 383.2 C: 1.73 D: 3.01 ¹H NMR (500MHz, DMSO-d₆) Shift 12.83 (s, 1H), 10.78 (s, 1H), 9.51 (s, 1H), 8.45 (d,J = 5.8 Hz, 1H), 8.35 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 8.2 Hz, 2H),7.96-7.87 (m, 3H), 7.77 (d, J = 7.3 Hz, 1H), 7.69 (d, J = 6.1 Hz, 1H),7.61 (d, J = 8.2 Hz, 2H) 111

6-methyl-4-oxo-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-4H,5H,6H,7H- furo[2,3-c]pyridine-3- carboxamide 415.1 112

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidine- 2-carboxamide 384.2 ¹H NMR (400 MHz,methanol-d₄) Shift 13.64 (br. s., 1H), 11.90 (s, 1H), 10.34 (dd, J =6.8, 2.0 Hz, 1H), 9.86 (dd, J = 4.3, 2.0 Hz, 1H), 9.20-9.11 (m, 1H),8.92 (d, J = 8.5 Hz, 2H), 8.77-8.67 (m, 2H), 8.60-8.54 (m, 1H),8.47-8.40 (m, 2H), 8.35 (dd, J = 6.8, 4.3 Hz, 1H) 113

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a]pyrimidine-3- carboxamide 383.1 ¹H NMR (400 MHz, methanol-d₄) Shift13.62 (s, 1H), 10.97 (s, 1H), 10.20 (dd, J = 6.9, 1.6 Hz, 1H), 9.75 (dd,J = 4.1, 1.6 Hz, 1H), 9.57 (s, 1H), 9.18-9.14 (m, 1H), 8.76- 8.68 (m,4H), 8.61-8.56 (m, 1H), 8.43 (d, J = 8.6 Hz, 2H), 8.17 (dd, J = 7.0, 4.0Hz, 1H) 114

5-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-indazole-3-carboxamide ¹H NMR (400 MHz, methanol-d₄) Shift 13.64 (br. s., 1H),11.36 (br. s., 1H), 9.19-9.13 (m, 1H), 8.99 (d, J = 1.8 Hz, 1H), 8.90(d, J = 8.8 Hz, 2H), 8.72 (quind, J = 7.4, 1.5 Hz, 2H), 8.62-8.53 (m,2H), 8.39 (d, J = 8.5 Hz, 2H), 8.19 (dd, J = 8.8, 1.8 Hz, 1H) 115

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1,3- benzothiazole-2-carboxamide 399.1 ¹H NMR (400 MHz, methanol-d₄) Shift 13.64 (s, 1H),12.14 (s, 1H), 9.19-9.14 (m, 1H), 9.12-9.04 (m, 2H), 8.96-8.90 (m, 2H),8.78-8.68 (m, 2H), 8.59-8.55 (m, 1H), 8.53-8.41 (m, 5H) 116

2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-4,5,6,7-tetrahydro-2H-indazole- 3-carboxamide 400.2 ¹H NMR (400 MHz,methanol-d₄) Shift 13.62 (br. s., 1H), 10.99 (s, 1H), 9.20-9.10 (m, 1H),8.75-8.65 (m, 3H), 8.58-8.53 (m, 1H), 8.47-8.32 (m, 3H), 4.71 (s, 3H),3.52 (t, J = 5.8 Hz, 2H), 3.39 (t, J = 5.9 Hz, 2H), 2.63-2.45 (m, 4H)117

4-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-3-carboxamide 411.2 C: 2.30 D: 3.56 ¹H NMR (400 MHz, DMSO-d₆) Shift 12.81(br. s., 1H), 10.84 (s, 1H), 8.39-8.32 (m, 1H), 8.07 (s, 1H), 7.97- 7.87(m, 4H), 7.81-7.77 (m, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.23-7.16 (m, 2H),6.88-6.82 (m, 1H), 4.15 (s, 3H) 118

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1,2- benzoxazole-3-carboxamide 383.2 C: 2.58 D: 3.82 ¹H NMR (400 MHz, DMSO-d₆) Shift 12.83(br. s., 1H), 11.24 (br. s., 1H), 8.38-8.33 (m, 1H), 8.19 (d, J = 8.0Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.97-7.87 (m, 3H), 7.83- 7.73 (m,2H), 7.67-7.62 (m, 2H), 7.60-7.54 (m, 1H) 119

5-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrrolo[2,3- b]pyridine-2-carboxamide 416.1 C: 2.30 D: 3.61120

5-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3- carboxamide 398.2 C: 2.04 D: 3.43 ¹H NMR (400 MHz,DMSO-d₆) Shift 12.80 (br. s., 1H), 10.09 (s, 1H), 8.60 (s, 1H),8.37-8.30 (m, 2H), 8.26 (dd, J = 9.4, 2.9 Hz, 1H), 7.99-7.86 (m, 5H),7.81-7.75 (m, 1H), 7.58 (d, J = 8.5 Hz, 2H) 121

6-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyrazine-2-carboxamide 397.1 122

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-3-carboxamide 395.2 123

5-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole-3-carboxamide 412.2 C: 2.23 D: 3.50 ¹H NMR (400 MHz, DMSO-d₆) Shift12.80 (s, 1H), 10.47 (s, 1H), 8.35 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 8.8Hz, 2H), 7.96-7.86 (m, 2H), 7.78 (d, J = 9.0 Hz, 1H), 7.64 (s, 1H),7.61-7.55 (m, 3H), 7.12 (d, J = 9.3 Hz, 1H), 3.85 (s, 3H) 124

8-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyrazine-2-carboxamide 415.2 C: 2.03 D: 3.25 ¹H NMR (400 MHz, DMSO-d₆)Shift 12.82 (br. s., 1H), 10.58 (br. s., 1H), 8.84 (s, 1H), 8.71 (d, J =4.5 Hz, 1H), 8.38-8.33 (m, 1H), 8.08 (d, J = 8.8 Hz, 2H), 7.92 (qd, J =7.2, 5.5 Hz, 2H), 7.86 (d, J = 4.5 Hz, 1H), 7.79-7.74 (m, 1H), 7.61 (d,J = 8.5 Hz, 2H) 125

5-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 411.3 C: 2.41 D: 3.63 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.83(br. s., 1H), 11.68 (br. s., 1H), 10.39 (br. s., 1H), 8.35 (d, J = 7.6Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.96-7.86 (m, 2H), 7.78 (d, J = 7.6Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.42-7.34 (m, 2H), 7.16 (s, 1H), 6.90(dd, J = 8.7, 1.4 Hz, 1H), 3.79 (s, 3H) 126

7-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyridine-2-carboxamide 396.3 C: 2.30 D: 3.50 ¹H NMR (500 MHz, DMSO-d₆)Shift 12.82 (s, 1H), 10.48 (s, 1H), 8.52 (d, J = 7.3 Hz, 1H), 8.48 (s,1H), 8.34 (d, J = 7.3 Hz, 1H), 8.10 (d, J = 8.5 Hz, 2H), 7.98-7.86 (m,2H), 7.76 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.44 (s, 1H),6.89 (d, J = 7.0 Hz, 1H), 2.40 (s, 3H) 127

6-methoxy-1-methyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-2- carboxamide 425.2 C: 2.71 D: 3.82 ¹H NMR (500MHz, DMSO-d₆) Shift 12.83 (s, 1H), 10.40 (s, 1H), 8.38-8.31 (m, 1H),7.97 (d, J = 8.5 Hz, 2H), 7.95- 7.86 (m, 2H), 7.77 (d, J = 7.3 Hz, 1H),7.62-7.54 (m, 3H), 7.34 (s, 1H), 7.07 (s, 1H), 6.80 (dd, J = 8.9, 2.1Hz, 1H), 4.01 (s, 3H), 3.86 (s, 3H) 128

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-6-(propan-2-yloxy)-1H-indole-2- carboxamide 439.3 C: 2.75 D: 3.89 ¹H NMR (500 MHz,DMSO-d₆) Shift 12.83 (s, 1H), 11.54 (br. s., 1H), 10.31 (s, 1H), 8.35(d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.96-7.86 (m, 3H), 7.78(d, J = 7.3 Hz, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H),7.41 (s, 1H), 6.93 (s, 1H), 6.72 (dd, J = 8.5, 1.8 Hz, 1H), 4.58 (dt, J= 12.2, 6.1 Hz, 1H), 1.30 (d, J = 6.1 Hz, 6H) 129

7-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 411.3 C: 2.54 D: 3.73 ¹H NMR (500 MHz, DMSO-d₆) Shift 12.84(s, 1H), 11.66 (s, 1H), 10.36 (s, 1H), 8.39-8.32 (m, 1H), 7.98 (d, J =8.5 Hz, 2H), 7.94-7.86 (m, 2H), 7.78 (d, J = 7.3 Hz, 1H), 7.62 (d, J =8.5 Hz, 2H), 7.34 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.03 (t, J = 7.9Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 3.96 (s, 3H) 130

5-ethoxy-1-methyl-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-2- carboxamide 439.2 C: 2.70 D: 3.90 ¹H NMR (500MHz, DMSO-d₆) Shift 12.84 (s, 1H), 10.49 (s, 1H), 8.40-8.29 (m, 1H),7.98 (d, J = 8.5 Hz, 2H), 7.94- 7.86 (m, 2H), 7.80-7.74 (m, 1H), 7.59(d, J = 8.5 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.27 (s, 1H), 7.17 (d, J= 2.1 Hz, 1H), 6.97 (dd, J = 8.9, 2.4 Hz, 1H), 4.05 (q, J = 6.9 Hz, 2H),4.01 (s, 3H), 1.36 (t, J = 6.9 Hz, 3H) 131

2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-2H-indazole-3-carboxamide 396.2 C: 2.16 D: 3.47 ¹H NMR (500 MHz, DMSO-d₆) Shift12.85 (br. s., 1H), 10.86 (br. s., 1H), 8.35 (d, J = 7.9 Hz, 1H),8.00-7.84 (m, 5H), 7.76 (t, J = 8.2 Hz, 2H), 7.63 (d, J = 8.2 Hz, 2H),7.38 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.2 Hz, 1H), 4.38 (s, 3H) 132

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(propan-2-yl)-1H-indazole-3- carboxamide 424.3 C: 2.93 D: 4.06 ¹H NMR (500 MHz,DMSO-d₆) Shift 12.84 (s, 1H), 10.29 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H),8.25 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.98-7.83 (m, 3H),7.79 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50 (t, J = 7.5 Hz,1H), 7.34 (t, J = 7.5 Hz, 1H), 5.16 (quin, J = 6.6 Hz, 1H), 1.62 (d, J =6.4 Hz, 6H) 133

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]pyrazine-2-carboxamide 383.1 C: 1.90 D: 3.05 ¹H NMR (500 MHz, DMSO-d₆)Shift 12.83 (s, 1H), 10.77 (s, 1H), 9.23 (s, 1H), 8.72 (s, 1H),8.70-8.64 (m, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.11 (d, J = 8.5 Hz, 2H),8.03 (d, J = 4.9 Hz, 1H), 7.95-7.86 (m, 2H), 7.76 (d, J = 7.3 Hz, 1H),7.59 (d, J = 8.2 Hz, 2H) 134

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5H,6H,7H,8H-imidazo[1,2-a]pyridine-2- carboxamide 386.2 C: 1.93 D: 3.21 ¹H NMR (500MHz, DMSO-d₆) Shift 12.80 (s, 1H), 9.99 (s, 1H), 8.34 (d, J = 6.7 Hz,1H), 8.03 (d, J = 8.5 Hz, 2H), 7.94-7.84 (m, 2H), 7.78-7.67 (m, 2H),7.53 (d, J = 8.5 Hz, 2H), 4.09-3.96 (m, 2H), 2.82 (t, J = 6.0 Hz, 2H),2.01- 1.81 (m, 4H) 135

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrrolo[2,3-b]pyridine-3- carboxamide 382.2 C: 2.03 D: 3.24 ¹H NMR (400MHz, DMSO-d₆) Shift 12.79 (br. s., 1H), 10.03 (s, 1H), 8.53 (dd, J =7.9, 1.6 Hz, 1H), 8.49 (s, 1H), 8.39-8.30 (m, 2H), 8.00-7.86 (m, 4H),7.81-7.76 (m, 1H), 7.62-7.54 (m, 2H), 7.24 (dd, J = 8.0, 4.8 Hz, 1H) 136

1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-2-carboxamide 471.4 C: 3.12 D: 4.22 ¹H NMR (400 MHz, DMSO-d₆) Shift 12.81(br. s., 1H), 10.60 (s, 1H), 8.39-8.29 (m, 1H), 7.99-7.93 (m, 2H),7.93-7.85 (m, 2H), 7.82-7.71 (m, 2H), 7.58 (d, J = 8.8 Hz, 3H), 7.47 (s,1H), 7.34-7.23 (m, 3H), 7.23-7.08 (m, 4H), 5.91 (s, 2H) 137

1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E: 1.64 F: 1.60 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.44 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.23 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.92 (t, J = 8.8 Hz,2H), 7.87 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.60 (d, J =8.0 Hz, 2H), 7.48 (t, J = 7.6 Hz, 1H), 7.32 (t, J = 7.3 Hz, 1H), 4.79(s, 1H), 4.49 (s, 2H), 1.19 (s, 6H) 138

1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-3- carboxamide 453.2 E: 1.65 F: 1.66 ¹H NMR (500MHz, DMSO-d₆) d 12.83 (br. s., 1H), 10.01 (br. s., 1H), 8.38 (br. s.,1H), 8.35 (d, J = 7.4 Hz, 1H), 8.24 (d, J = 6.9 Hz, 1H), 7.97 (d, J =8.0 Hz, 2H), 7.95-7.86 (m, 2H), 7.80 (d, J = 6.9 Hz, 1H), 7.66 (d, J =8.0 Hz, 1H), 7.57 (d, J = 7.7 Hz, 2H), 7.28-7.12 (m, 2H), 4.85 (br. s.,1H), 4.17 (br. s., 2H), 1.15 (br. s., 6H) 139

2,7-dimethyl-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]imidazo[1,2- a]pyridine-3-carboxamide 410.2 E: 1.09 F: 1.43140

2-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]imidazo[1,2-a]pyrimdine-3- carboxamide 411.2 E: 1.15 F: 1.46 ¹H NMR (500 MHz, DMSO-d₆)d 12.83 (s, 1H), 10.33 (s, 1H), 9.25 (dd, J = 6.9, 1.9 Hz, 1H), 8.67(dd, J = 4.1, 1.9 Hz, 1H), 8.38-8.33 (m, 1H), 7.97-7.87 (m, 4H),7.79-7.75 (m, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.22 (dd, J = 6.7, 4.3 Hz,1H), 3.11 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H) 141

6-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide 412.1 E: 1.41 F: 1.41 ¹H NMR (500 MHz, DMSO-d₆)d 12.81 (s, 1H), 10.11 (s, 1H), 8.74 (s, 1H), 8.55 (d, J = 1.9 Hz, 1H),8.35 (dd, J = 7.7, 1.4 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.96 (d, J =8.5 Hz, 2H), 7.91 (ddd, J = 9.6, 7.6, 1.5 Hz, 2H), 7.81-7.76 (m, 1H),7.58 (d, J = 8.5 Hz, 2H), 7.36 (dd, J = 9.6, 2.2 Hz, 1H), 3.88 (s, 3H)142

1-[2-(dimethylamino) ethyl]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 453.2 E: 1.37 F: 1.41 ¹H NMR (500MHz, DMSO-d₆) d 12.84 (s, 1H), 10.42 (s, 1H), 9.44 (br. s., 1H), 8.36(d, J = 7.4 Hz, 1H), 8.29 (d, J = 8.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H),7.96-7.89 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7.67-7.55 (m, 3H), 7.41 (t,J = 7.6 Hz, 1H), 4.96 (br. s., 2H), 3.77 (br. s., 2H), 3.02- 2.85 (m,6H) 143

2-(oxetan-3-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-2H-indazole- 3-carboxamide 452.2 E: 1.14 F: 1.14 ¹H NMR (500MHz, DMSO-d₆) d 12.87 (s, 1H), 11.37 (s, 1H), 8.39-8.35 (m, 1H), 8.31(d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.02-7.89 (m, 5H), 7.74(d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.5 Hz, 3H), 5.23-5.15 (m, 2H), 4.97-4.88 (m, 2H), 4.70 (dd, J = 11.3, 5.0 Hz, 1H), 3.73 (br. s., 2H),3.68-3.58 (m, 1H) 144

1-(oxetan-3-ylmethyl)-N- (4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl)-1H-indazole- 3-carboxamide 452.1 E: 1.15 F: 1.14 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.40 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.25 (d, J = 8.0 Hz, 1H), 8.15-8.05 (m, J = 8.3 Hz, 2H), 7.97-7.88 (m,3H), 7.78 (d, J = 8.0 Hz, 1H), 7.64-7.58 (m, J = 8.5 Hz, 2H), 7.53 (t, J= 7.7 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.89 (d, J = 7.2 Hz, 2H),4.78-4.67 (m, 2H), 4.55 (t, J = 6.1 Hz, 2H), 3.68- 3.56 (m, 1H) 145

1-[(3-methyloxetan-3- yl)methyl]-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 466.2 E: 1.63 F: 1.62 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.36 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H),8.26 (d, J = 8.3 Hz, 1H), 8.13-8.02 (m, J = 8.0 Hz, 2H), 8.00-7.85 (m,3H), 7.77 (d, J = 7.7 Hz, 1H), 7.63-7.58 (m, J = 8.0 Hz, 2H), 7.53 (t, J= 7.6 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.80 (br. s., 4H), 4.33 (d, J =5.8 Hz, 2H), 1.20 (s, 3H) 146

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-ylmethyl)-1H-indazole-3- carboxamide 466.2 E: 1.63 F: 1.64 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.46 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H),8.26 (d, J = 8.0 Hz, 1H), 8.13-8.04 (m, J = 7.7 Hz, 2H), 7.96-7.87 (m,3H), 7.78 (d, J = 7.7 Hz, 1H), 7.67-7.57 (m, J = 8.0 Hz, 2H), 7.53 (t, J= 7.7 Hz, 1H), 7.35 (t, J = 7.3 Hz, 1H), 4.57 (d, J = 7.4 Hz, 2H), 3.86(d, J = 7.2 Hz, 1H), 3.74-3.64 (m, 2H), 3.59 (br. s., 1H), 3.05-2.94 (m,1H), 1.95 (dd, J = 11.8, 7.2 Hz, 1H), 1.72 (dd, J = 12.2, 6.5 Hz, 1H)147

1-[3-(benzyloxy)-2- hydroxypropyl]-N-[4-(4- oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 546.2 E: 1.95F: 1.95 ¹H NMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.48 (s, 1H),8.39-8.33 (m, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.10- 8.05 (m, 2H),7.98-7.87 (m, 2H), 7.83-7.74 (m, 2H), 7.62-7.58 (m, 2H), 7.48 (ddd, J =8.3, 7.1, 0.8 Hz, 1H), 7.39-7.35 (m, 4H), 7.35-7.32 (m, 1H), 7.32-7.27(m, 1H), 5.24 (d, J = 5.5 Hz, 1H), 4.71-4.61 (m, 1H), 4.59- 4.51 (m,3H), 4.31-4.21 (m, 1H), 3.51 (d, J = 5.5 Hz, 2H) 148

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(oxolan-2-ylmethyl)-1H-indazole-3- carboxamide 466.3 E: 1.84 F: 1.83 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.49 (s, 1H), 8.37-8.34 (m, 1H), 8.25(d, J = 8.3 Hz, 1H), 8.12- 8.07 (m, 2H), 7.97-7.88 (m, 2H), 7.84 (d, J =8.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.63-7.57 (m, 2H), 7.50 (ddd, J = 8.4,7.0, 1.1 Hz, 1H), 7.33 (td, J = 7.5, 0.7 Hz, 1H), 4.62 (d, J = 5.8 Hz,2H), 4.40 (t, J = 6.3 Hz, 1H), 3.81-3.72 (m, 1H), 3.62 (dt, J = 8.2, 6.8Hz, 1H), 2.12-1.92 (m, 1H), 1.88-1.79 (m, 2H), 1.78-1.68 (m, 1H) 149

1-(2,3-dihydroxypropyl)- N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 456.2 E: 1.40 F: 1.38 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.49 (s, 1H), 8.38-8.33 (m, 1H), 8.25(d, J = 8.3 Hz, 1H), 8.12- 8.09 (m, 1H), 8.09-8.07 (m, 1H), 7.97-7.89(m, 2H), 7.82-7.76 (m, 2H), 7.62-7.58 (m, 2H), 7.49 (ddd, J = 8.4, 7.0,1.1 Hz, 1H), 7.35-7.30 (m, 1H), 5.04 (d, J = 5.2 Hz, 1H), 4.86 (t, J =5.6 Hz, 1H), 4.66 (dd, J = 14.2, 3.7 Hz, 1H), 4.48 (dd, J = 14.2, 8.1Hz, 1H), 4.13-4.03 (m, 1H), 3.53-3.40 (m, 2H) 150

1-(oxan-4-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 480.0 E: 1.80 F: 1.79 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.47 (s, 1H), 8.35 (dd, J = 7.6, 1.2 Hz,1H), 8.25 (d, J = 8.3 Hz, 1H), 8.15-8.05 (m, J = 8.5 Hz, 2H), 7.94-7.84(m, 3H), 7.82- 7.74 (m, 1H), 7.63-7.56 (m, J = 8.5 Hz, 2H), 7.55-7.47(m, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.48 (d, J = 7.2 Hz, 2H), 3.88-3.76(m, 2H), 3.29-3.18 (m, 2H), 2.37-2.21 (m, 1H), 1.50-1.26 (m, 4H) 151

1-(2-methoxyethyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 440.2 E: 1.73 F: 1.73 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.49 (s, 1H), 8.35 (dd, J = 7.8, 1.2 Hz,1H), 8.25 (d, J = 8.3 Hz, 1H), 8.13-8.06 (m, 2H), 7.95-7.88 (m, 2H),7.84 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 7.8, 1.0 Hz, 1H), 7.64-7.58 (m,2H), 7.50 (ddd, J = 8.4, 7.2, 1.0 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H),4.75 (t, J = 5.4 Hz, 2H), 3.88 (t, J = 5.2 Hz, 2H), 3.23 (s, 3H) 152

1-(oxetan-2-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 452.2 E: 1.61 F: 1.61 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.50 (s, 1H), 8.35 (dd, J = 7.6, 1.2 Hz,1H), 8.25 (d, J = 8.3 Hz, 1H), 8.14-8.05 (m, J = 8.5 Hz, 2H), 7.97-7.88(m, 3H), 7.80- 7.74 (m, 1H), 7.64-7.57 (m, J = 8.5 Hz, 2H), 7.50 (dd, J= 8.5, 1.1 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 5.33-5.15 (m, 1H), 4.90(dd, J = 14.9, 6.3 Hz, 1H), 4.80 (dd, J = 14.9, 3.9 Hz, 1H), 4.48 (ddd,J = 8.4, 7.0, 5.8 Hz, 1H), 4.30 (dt, J = 9.0, 5.9 Hz, 1H), 2.78-2.72 (m,1H), 2.60-2.54 (m, 1H) 153

1-(2-hydroxypropyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)pheyl]-1H-indazole- 3-carboxamide 440.2 E: 1.55 F: 1.55 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.51 (s, 1H), 8.35 (dd, J = 7.8, 1.2 Hz,1H), 8.24 (d, J = 8.3 Hz, 1H), 8.12-8.06 (m, J = 8.5 Hz, 2H), 7.97-7.87(m, 2H), 7.83 (d, J = 8.5 Hz, 1H), 7.79-7.75 (m, 1H), 7.62-7.57 (m, J =8.5 Hz, 2H), 7.53-7.46 (m, 1H), 7.32 (t, J = 7.4 Hz, 1H), 5.02 (d, J =5.0 Hz, 1H), 4.47 (d, J = 6.1 Hz, 2H), 4.32-4.19 (m, 1H), 1.16 (d, J =6.3 Hz, 3H) 154

1-[2-(2-methoxyethoxy) ethyl]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 484.3 E: 1.66 F: 1.66 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.54 (s, 1H), 8.35 (dd, J = 7.8, 1.2 Hz,1H), 8.25 (d, J = 8.3 Hz, 1H), 8.14-8.06 (m, J = 8.5 Hz, 2H), 8.00-7.89(m, 2H), 7.86 (d, J = 8.5 Hz, 1H), 7.83-7.75 (m, 1H), 7.65-7.58 (m, J =8.5 Hz, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.75(t, J = 5.4 Hz, 2H), 3.96 (t, J = 5.4 Hz, 2H), 3.51 (dd, J = 5.6, 3.7Hz, 2H), 3.13 (s, 3H) 155

1-(2-hydroxyethyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 426.2 E: 1.43 F: 1.42 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.53 (s, 1H), 8.35 (dd, J = 7.7, 1.4 Hz,1H), 8.25 (d, J = 8.3 Hz, 1H), 8.13-8.07 (m, J = 8.5 Hz, 2H), 7.97-7.88(m, 2H), 7.82 (d, J = 8.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.62-7.58 (m, J =8.5 Hz, 2H), 7.52-7.47 (m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 4.98 (t, J =5.5 Hz, 1H), 4.62 (t, J = 5.4 Hz, 2H), 3.94 (q, J = 5.5 Hz, 2H) 156

1-[2-(oxan-4-yl)ethyl]-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 494.3 E: 1.96 F: 1.92 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.50 (s, 1H), 8.38-8.33 (m, 1H), 8.26(d, J = 8.3 Hz, 1H), 8.12- 8.07 (m, J = 8.5 Hz, 2H), 7.97-7.89 (m, 2H),7.85 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.63-7.57 (m, J =8.5 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.62(t, J = 7.4 Hz, 2H), 3.83 (dd, J = 11.3, 3.0 Hz, 2H), 3.25 (t, J = 11.0Hz, 2H), 1.96-1.87 (m, 2H), 1.67 (d, J = 12.9 Hz, 2H), 1.53 (ddt, J =14.4, 7.2, 3.8 Hz, 1H), 1.26 (qd, J = 12.2, 4.5 Hz, 2H) 157

1-[2-(benzyloxy)ethyl]-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 516.3 E: 2.08 F: 2.11 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.53 (s, 1H), 8.37-8.33 (m, 1H), 8.26(d, J = 8.0 Hz, 1H), 8.12- 8.07 (m, J = 8.5 Hz, 2H), 7.96-7.84 (m, 3H),7.78 (d, J = 7.7 Hz, 1H), 7.64-7.58 (m, J = 8.5 Hz, 2H), 7.50 (t, J =7.7 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.27-7.19 (m, 3H), 7.15-7.10 (m,2H), 4.81 (t, J = 5.1 Hz, 2H), 4.47 (s, 2H), 3.97 (t, J = 5.2 Hz, 2H)158

6-fluoro-1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 472.2 E: 1.65F: 1.66 ¹H NMR (500 MHz, DMSO-d₆) d 12.85 (s, 1H), 10.49 (s, 1H), 8.35(dd, J = 7.7, 1.4 Hz, 1H), 8.23 (dd, J = 8.8, 5.5 Hz, 1H), 8.09-8.05 (m,J = 8.8 Hz, 2H), 7.97-7.89 (m, 2H), 7.80-7.76 (m, 1H), 7.73 (dd, J =9.9, 1.9 Hz, 1H), 7.63- 7.58 (m, J = 8.8 Hz, 2H), 7.21 (td, J = 9.1, 1.9Hz, 1H), 4.45 (s, 2H), 1.19 (s, 6H) 159

6-fluoro-1-(oxetan-3- ylmethyl)-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 470.3 E: 1.74 F: 1.71 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.48 (s, 1H), 8.41-8.31 (m, 1H), 8.24(dd, J = 8.9, 5.4 Hz, 1H), 8.15-8.01 (m, J = 8.5 Hz, 2H), 8.01-7.85 (m,3H), 7.77 (d, J = 7.7 Hz, 1H), 7.66-7.52 (m, J = 8.5 Hz, 2H), 7.24 (td,J = 9.1, 1.9 Hz, 1H), 4.85 (d, J = 7.4 Hz, 2H), 4.69 (dd, J = 7.7, 6.3Hz, 2H), 4.54 (t, J = 6.2 Hz, 2H), 3.71-3.54 (m, 1H) 160

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(pyridin-2-ylmethyl)-1H-indazole-3- carboxamide 473.3 A: 10.97 B: 10.36 ¹H NMR (400MHz, DMSO-d₆) d 12.82 (s, 1H), 10.59 (s, 1H), 8.62-8.49 (m, 1H),8.42-8.23 (m, 2H), 8.14-8.04 (m, 2H), 7.94-7.88 (m, 2H), 7.84-7.73 (m,3H), 7.61- 7.56 (m, 2H), 7.50 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H), 7.38-7.31 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 5.97 (s, 2H) 161

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(pyridin-3-ylmethyl)-1H-indazole-3- carboxamide 473.3 A: 8.60 B: 9.15 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.57 (s, 1H), 8.77 (d, J = 4.1 Hz, 1H),8.62 (br. s., 1H), 8.42-8.33 (m, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.09 (d,J = 8.8 Hz, 2H), 7.98-7.89 (m, 3H), 7.89-7.83 (m, 1H), 7.82-7.74 (m,1H), 7.60 (d, J = 8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.37 (t, J = 7.6 Hz,1H), 5.94 (s, 2H) 162

1-[3-(benzyloxy)propyl]- N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 530.3 E: 2.15 F: 2.14 ¹H NMR (500MHz, DMSO-d₆) d 12.84 (s, 1H), 10.52 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.26 (d, J = 8.3 Hz, 1H), 8.12- 8.07 (m, J = 8.3 Hz, 2H), 7.97-7.87 (m,2H), 7.79 (t, J = 9.5 Hz, 2H), 7.62-7.56 (m, J = 8.5 Hz, 2H), 7.50 (t, J= 7.7 Hz, 1H), 7.37-7.27 (m, 6H), 4.67 (t, J = 6.9 Hz, 2H), 4.44 (s,2H), 3.45 (t, J = 5.9 Hz, 2H), 2.24 (t, J = 6.5 Hz, 2H) 163

1-(3-methoxypropyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E: 1.78 F: 1.77 ¹H NMR (500MHz, DMSO-d₆) d 12.84 (s, 1H), 10.53 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.26 (d, J = 8.3 Hz, 1H), 8.13- 8.06 (m, J = 8.5 Hz, 2H), 7.98-7.89 (m,2H), 7.79 (t, J = 9.1 Hz, 2H), 7.64-7.57 (m, J = 8.3 Hz, 2H), 7.51 (d, J= 8.0 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 4.63 (t, J = 6.9 Hz, 2H), 3.32-3.29 (m, 2H), 3.22 (s, 3H), 2.18 (t, J = 6.5 Hz, 2H) 164

1-(3-hydroxypropyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 440.3 E: 1.48 F: 1.48 ¹H NMR (500MHz, DMSO-d₆) d 12.84 (s, 1H), 10.52 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H),8.25 (d, J = 8.3 Hz, 1H), 8.15- 8.08 (m, J = 8.3 Hz, 2H), 7.96-7.86 (m,2H), 7.82 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.62-7.57 (m, J= 8.3 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.70(t, J = 5.0 Hz, 1H), 4.64 (t, J = 7.0 Hz, 2H), 3.45 (q, J = 5.8 Hz, 2H),2.09 (t, J = 6.6 Hz, 2H) 165

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(pyridin-4-ylmethyl)-1H-indazole-3- carboxamide 473.3 E: 1.20 F: 1.58 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.65 (s, 1H), 8.65 (d, J = 5.2 Hz, 2H),8.32 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.16-8.03 (m, J =8.3 Hz, 2H), 7.98- 7.89 (m, 2H), 7.84 (d, J = 8.5 Hz, 1H), 7.77 (d, J =7.7 Hz, 1H), 7.64-7.58 (m, J = 8.3 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H),7.43-7.35 (m, 3H), 6.04 (s, 2H) 166

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrrolo[3,2-c]pyridine-3- carboxamide 382.2 E: 0.96 F: 1.03 ¹H NMR (500 MHz,DMSO-d₆) d 13.18 (br. s., 1H), 12.86 (s, 1H), 10.46 (s, 1H), 9.58 (br.s., 1H), 8.81 (s, 1H), 8.52 (d, J = 6.1 Hz, 1H), 8.35 (d, J = 8.0 Hz,1H), 8.05 (d, J = 6.3 Hz, 1H), 8.01-7.97 (m, J = 8.3 Hz, 2H), 7.96-7.87(m, 2H), 7.78 (d, J = 7.7 Hz, 1H), 7.66-7.60 (m, J = 8.3 Hz, 2H), 6.57(br. s., 1H) 167

5-fluoro-1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 472.2 E: 1.63F: 1.64 ¹H NMR (500 MHz, DMSO-d₆) d 12.85 (s, 1H), 10.49 (s, 1H), 8.35(d, J = 7.7 Hz, 1H), 8.12-8.05 (m, J = 8.3 Hz, 2H), 7.99-7.90 (m, 3H),7.86 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.63-7.57 (m, J =8.3 Hz, 2H), 7.41 (t, J = 9.1 Hz, 1H), 4.81 (s, 1H), 4.49 (s, 2H), 1.19(s, 6H) 168

1-(oxan-2-ylmethyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indazole- 3-carboxamide 480.2 E: 2.04 F: 2.04 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 10.53 (s, 1H), 8.35 (d, J = 7.4 Hz, 1H),8.24 (d, J = 8.3 Hz, 1H), 8.14- 8.08 (m, J = 8.0 Hz, 2H), 7.97-7.87 (m,2H), 7.87-7.73 (m, 2H), 7.66-7.57 (m, J = 8.0 Hz, 2H), 7.49 (t, J = 7.8Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H), 4.69-4.57 (m, 1H), 4.57- 4.47 (m,1H), 3.98-3.84 (m, 2H), 3.79 (d, J = 11.0 Hz, 1H), 3.29-3.18 (m, 1H),1.88-1.76 (m, 1H), 1.65 (d, J = 12.4 Hz, 1H), 1.50-1.29 (m, 4H) 169

1-(2-hydroxy-2- methylpropyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrrolo [2,3-b]pyridine-3- carboxamide 454.2 E: 1.41 F:1.46 ¹H NMR (500 MHz, DMSO-d₆) d 12.84 (s, 1H), 10.18 (s, 1H), 8.61 (s,1H), 8.56 (d, J = 7.7 Hz, 1H), 8.38-8.32 (m, 2H), 8.02-7.95 (m, J = 8.0Hz, 2H), 7.95-7.85 (m, 2H), 7.79 (d, J = 7.7 Hz, 1H), 7.63-7.55 (m, J =8.0 Hz, 2H), 7.33-7.23 (m, 1H), 4.30 (s, 2H), 1.11 (s, 6H) 170

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-[3-ylmethyl]-1H-indazole-3- carboxamide 466.3 E: 1.80 F: 1.80 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (br. s., 1H), 10.46 (br. s., 1H), 8.35 (d, J = 6.6Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 8.11-8.04 (m, J = 7.7 Hz, 2H),7.98-7.86 (m, 3H), 7.78 (d, J = 7.2 Hz, 1H), 7.62-7.57 (m, J = 8.0 Hz,2H), 7.53 (br. s., 1H), 7.35 (br. s., 1H), 4.57 (d, J = 6.3 Hz, 2H),3.88-3.80 (m, 1H), 3.72-3.64 (m, 2H), 3.60-3.53 (m, 1H), 2.96 (br. s.,1H), 1.94 (br. s., 1H), 1.72 (br. s., 1H) 171

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-[oxolan-3-ylmethyl]-1H-indazole-3- carboxamide 466.3 E: 1.80 F: 1.80 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (br. s., 1H), 10.46 (br. s., 1H), 8.35 (d, J = 6.9Hz, 1H), 8.26 (d, J = 7.7 Hz, 1H), 8.12-8.03 (m, J = 7.7 Hz, 2H),7.98-7.84 (m, 3H), 7.78 (d, J = 6.9 Hz, 1H), 7.65-7.57 (m, J = 7.7 Hz,2H), 7.56-7.46 (m, 1H), 7.39-7.27 (m, 1H), 4.57 (d, J = 6.6 Hz, 2H),3.88-3.80 (m, 1H), 3.73-3.64 (m, 2H), 3.63- 3.54 (m, 1H), 2.96 (br. s.,1H), 1.94 (br. s., 1H), 1.72 (br. s., 1H) 172

6-(2-hydroxy-2- methylpropoxy)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 470.1 E: 1.44 F: 1.44 ¹HNMR (500 MHz, DMSO-d₆) d 12.84 (br. s., 1H), 10.12 (br. s., 1H), 8.74(br. s., 1H), 8.55 (br. s., 1H), 8.35 (d, J = 7.2 Hz, 1H), 8.19 (d, J =9.6 Hz, 1H), 7.99-7.86 (m, 4H), 7.78 (d, J = 7.4 Hz, 1H), 7.59 (d, J =8.0 Hz, 2H), 7.38 (d, J = 9.6 Hz, 1H), 4.74 (br. s., 1H), 4.12 (br. s.,1H), 3.83 (br. s., 2H), 3.16 (br. s., 2H), 1.23 (br. s., 6H) 173

5-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-ylmethyl)-1H-indazole-3- carboxamide 484.2 E: 1.81 F: 1.81 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (br. s., 1H), 10.50 (br. s., 1H), 8.35 (br. s.,1H), 8.07 (d, J = 6.6 Hz, 2H), 8.03- 7.94 (m, 1H), 7.90 (br. s., 3H),7.78 (br. s., 1H), 7.60 (d, J = 6.6 Hz, 2H), 7.53-7.39 (m, 1H), 4.58(br. s., 2H), 3.85 (br. s., 1H), 3.69 (d, J = 8.0 Hz, 2H), 3.57 (br. s.,1H), 2.94 (br. s., 1H), 1.95 (br. s., 1H), 1.71 (br. s., 1H) 174

6-fluoro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-ylmethyl)-1H-indazole-3- carboxamide 484.3 E: 1.83 F: 1.83 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (br. s., 1H), 10.50 (br. s., 1H), 8.34 (br. s.,1H), 8.26 (br. s., 1H), 8.07 (d, J = 7.2 Hz, 2H), 7.91 (br. s., 2H),7.83 (d, J = 9.9 Hz, 1H), 7.78 (br. s., 1H), 7.60 (d, J = 6.9 Hz, 2H),7.24 (t, J = 8.5 Hz, 1H), 4.53 (br. s., 2H), 3.85 (br. s., 1H),3.75-3.63 (m, 2H), 3.57 (br. s., 1H), 2.94 (br. s., 1H), 1.94 (br. s.,1H), 1.71 (br. s., 1H) 175

6-(2-methoxyethoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 456.2 E: 1.45 F: 1.45 ¹HNMR (500 MHz, DMSO-d₆) d 12.81 (br. s., 1H), 10.11 (br. s., 1H), 8.74(br. s., 1H), 8.57 (br. s., 1H), 8.35 (br. s., 1H), 8.18 (d, J = 9.4 Hz,1H), 7.98-7.88 (m, 4H), 7.79 (br. s., 1H), 7.58 (d, J = 5.2 Hz, 2H),7.37 (d, J = 9.6 Hz, 1H), 4.21 (br. s., 2H), 3.71 (br. s., 2H) 176

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]-6-[2-(pyrrolidin-1-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carboxamide 495.3 E: 1.05 F: 1.05¹H NMR (500 MHz, DMSO-d₆) d 12.81 (s, 1H), 10.12 (s, 1H), 8.75 (s, 1H),8.63 (s, 1H), 8.35 (dd, J = 7.6, 1.5 Hz, 1H), 8.21 (d, J = 9.6 Hz, 1H),8.02-7.90 (m, 3H), 7.79- 7.74 (m, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.39(dd, J = 9.6, 1.9 Hz, 1H), 4.28 (br. s., 2H), 2.89 (s, 4H), 1.82 (br.s., 4H) 177

6-[2-(dimethylamino) ethoxy]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 469.2 E: 1.04 F: 1.05¹H NMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.14 (s, 1H), 8.78 (s, 1H),8.70 (d, J = 1.7 Hz, 1H), 8.40-8.32 (m, 1H), 8.24 (d, J = 9.6 Hz, 1H),8.00-7.87 (m, 4H), 7.77 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H),7.41 (dd, J = 9.5, 2.1 Hz, 1H), 4.45 (t, J = 5.0 Hz, 2H), 3.57 (t, J =4.7 Hz, 2H), 2.96-2.87 (m, 6H) 178

5-fluoro-1-(2- methylprop-1-en-1-yl)-N- [4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E: 1.71F: 1.71 ¹H NMR (500 MHz, DMSO-d₆) d 12.84 (s, 1H), 10.79 (s, 1H), 8.35(dd, J = 7.8, 1.5 Hz, 1H), 7.97-7.85 (m, 5H), 7.79-7.74 (m, 1H), 7.63(d, J = 8.5 Hz, 2H), 7.56 (dd, J = 9.5, 2.3 Hz, 1H), 7.33 (td, J = 9.3,2.3 Hz, 1H), 7.29- 7.24 (m, 1H), 1.97-1.86 (m, 3H), 1.79 (d, J = 1.1 Hz,3H) 179

6-fluoro-1-(2- methylprop-1-en-1-yl)-N- [4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole- 3-carboxamide 454.2 E: 1.71F: 1.71 ¹H NMR (500 MHz, DMSO-d₆) d 12.84 (s, 1H), 10.92 (s, 1H),8.39-8.31 (m, 1H), 7.96-7.88 (m, 5H), 7.79-7.72 (m, 1H), 7.66-7.59 (m,2H), 7.54 (dd, J = 10.2, 1.9 Hz, 1H), 7.27-7.23 (m, 1H), 7.21-7.15 (m,1H), 1.92 (d, J = 1.4 Hz, 3H), 1.80 (d, J = 1.4 Hz, 3H) 180

6-fluoro-5-methoxy-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1-benzofuran- 2-carboxamide 430.1 E: 1.61 F: 1.61 ¹H NMR (500MHz, DMSO-d₆) d 12.83 (s, 1H), 10.71 (s, 1H), 8.40-8.31 (m, 1H),8.06-7.96 (m, J = 8.5 Hz, 2H), 7.95-7.87 (m, 2H), 7.79 (s, 1H),7.77-7.70 (m, 2H), 7.63- 7.58 (m, J = 8.8 Hz, 2H), 7.56 (d, J = 8.8 Hz,1H), 3.92 (s, 3H) 181

5-(2-hydroxy-2- methylpropoxy)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 470.1 A: 6.62 B: 5.93¹H NMR (400 MHz, DMSO-d₆) d 12.81 (s, 1H), 10.03 (s, 1H), 8.75 (s, 1H),8.69 (d, J = 7.5 Hz, 1H), 8.38-8.30 (m, 1H), 8.02-7.86 (m, 4H),7.81-7.75 (m, 1H), 7.65-7.53 (m, 3H), 6.82 (dd, J = 7.5, 2.6 Hz, 1H),1.25 (s, 6H) 182

5-methoxy-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide 412.1 E: 1.30 F: 1.37 ¹H NMR (500 MHz, DMSO-d₆)d 10.08 (s, 1H), 8.71 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.33 (d, J =7.3 Hz, 1H), 7.96- 7.86 (m, 4H), 7.76 (d, J = 7.9 Hz, 1H), 7.64-7.52 (m,3H), 6.90-6.74 (m, 1H), 3.70-3.57 (m, 3H) 183

N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl) phenyl]-5-[2-(pyrrolidin-1-yl)ethoxy]pyrazolo[1,5- a]pyridine-3-carboxamide 495.2 E: 1.08 F: 1.07¹H NMR (500 MHz, DMSO-d₆) d 10.08 (br. s., 1H), 8.71 (br. s., 1H), 8.64(d, J = 7.3 Hz, 1H), 8.33 (d, J = 6.7 Hz, 1H), 7.98-7.83 (m, 4H), 7.75(d, J = 7.0 Hz, 1H), 7.63- 7.52 (m, 3H), 6.79 (d, J = 4.9 Hz, 1H), 4.20(br. s., 2H), 3.65-3.42 (m, 4H), 2.87 (d, J = 4.6 Hz, 2H), 1.86 (br. s.,1H), 1.68 (br. s., 4H) 184

5-(2-methoxyethoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 456.1 E: 1.37 F: 1.35¹H NMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.07 (s, 1H), 8.71 (s, 1H),8.65 (d, J = 7.3 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 8.03-7.83 (m, 4H),7.76 (d, J = 7.3 Hz, 1H), 7.63- 7.47 (m, 3H), 6.80 (d, J = 7.3 Hz, 1H),4.22 (br. s., 2H), 3.72 (br. s., 1H), 3.62 (br. s., 1H), 3.58 (d, J =7.6 Hz, 3H) 185

5-(2-hydroxypropoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 456.2 E: 1.26 F: 1.26 ¹HNMR (500 MHz, DMSO-d₆) d 12.84 (s, 1H), 10.07 (s, 1H), 8.80-8.60 (m,2H), 8.34 (d, J = 7.4 Hz, 1H), 7.97- 7.87 (m, 4H), 7.77 (d, J = 7.7 Hz,1H), 7.67-7.52 (m, 3H), 6.86-6.75 (m, 1H), 4.11-3.91 (m, 2H), 3.67-3.41(m, 1H), 1.39-1.14 (m, 3H) 186

5-(2-hydroxyethoxy)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 412.2 E: 1.15 F: 1.15 ¹HNMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 10.05 (s, 1H), 8.75 (s, 1H),8.70 (d, J = 7.4 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.03-7.84 (m, 4H),7.78 (d, J = 7.7 Hz, 1H), 7.64- 7.50 (m, 3H), 6.81 (dd, J = 7.4, 2.7 Hz,1H), 4.14 (t, J = 4.7 Hz, 2H), 3.79 (d, J = 4.4 Hz, 2H) 187

5-[2-(morpholin-4- yl)ethoxy]-N-[4-(4-oxo- 3,4-dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5- a]pyridine-3-carboxamide 511.1 E: 1.30 F: 1.06¹H NMR (500 MHz, DMSO-d₆) d 10.10 (s, 1H), 8.76 (s, 1H), 8.69 (d, J =7.4 Hz, 1H), 8.35 (d, J = 7.4 Hz, 1H), 8.02- 7.87 (m, 4H), 7.78 (d, J =7.7 Hz, 1H), 7.63 (br. s., 1H), 7.57 (d, J = 8.1 Hz, 2H), 6.81 (d, J =5.0 Hz, 1H), 4.23 (t, J = 5.2 Hz, 2H), 2.82-2.73 (m, 2H) 188

6-[2-(morpholin-4-yl) ethoxy]-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide 511.1 E: 1.34 F: 1.07 ¹HNMR (500 MHz, DMSO-d₆) d 10.13 (br. s., 1H), 8.74 (br. s., 1H), 8.58(br. s., 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.17 (d, J = 9.8 Hz, 1H),7.99-7.87 (m, 4H), 7.78 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.7 Hz, 2H),7.37 (d, J = 9.8 Hz, 1H), 4.19 (br. s., 2H), 3.59 (br. s., 4H), 2.73 (d,J = 5.0 Hz, 2H) 189

5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-4-carboxamide 422.2 E: 1.51 F: 1.51 (500 MHz, DMSO-d₆) δ ppm12.84 (s, 1H), 10.10 (s, 1H), 8.51-8.26 (m, 2H), 8.01-7.87 (m, 4H), 7.76(d, J = 7.7 Hz, 1H), 7.64-7.42 (m, 7H), 2.57 (s, 3H) 190

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-(trifluoromethyl)-1H- pyrazole-4-carboxamide 476.3 E: 1.67 F: 1.67 (500MHz, DMSO-d₆) δ ppm 12.85 (s, 1H), 10.78 (s, 1H), 8.35 (br. s., 2H),7.89 (d, J = 8.1 Hz, 4H), 7.75 (d, J = 7.1 Hz, 1H), 7.67-7.59 (m, 5H),7.56 (br. s., 2H) 191

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-4-carboxamide 408.3 E: 1.48 F: 1.47 (500 MHz, DMSO-d₆) δ ppm12.85 (s, 1H), 10.23 (s, 1H), 9.14 (s, 1H), 8.55-8.17 (m, 2H), 7.92 (dd,J = 13.6, 8.2 Hz, 6H), 7.77 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 8.4 Hz,2H), 7.56 (t, J = 7.9 Hz, 2H), 7.44-7.30 (m, 1H) 192

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-5-phenyl-1H-pyrazole-4-carboxamide 422.3 E: 1.38 F: 1.38 (500 MHz, DMSO-d₆) δ ppm12.81 (s, 1H), 9.97 (s, 1H), 8.33 (d, J = 7.1 Hz, 1H), 8.19 (s, 1H),7.94 (s, 1H), 7.92- 7.84 (m, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.72 (d, J =7.4 Hz, 1H), 7.56-7.43 (m, 6H), 3.71 (s, 3H) 193

3-(3-chloro-2- fluorophenyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-4,5-dihydro-1,2- oxazole-5-carboxamide 463.2 E: 1.69 F: 1.70 ¹HNMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 10.57 (s, 1H), 8.33 (d, J = 7.1Hz, 1H), 7.93-7.80 (m, 4H), 7.80- 7.67 (m, 3H), 7.57 (d, J = 8.4 Hz,2H), 7.34 (t, J = 7.9 Hz, 1H), 5.42-5.32 (m, 1H), 3.81 (d, J = 10.4 Hz,2H), 3.39 (d, J = 5.7 Hz, 1H) 194

5-(2-hydroxy-3- methoxypropoxy)-N-[4- (4-oxo-3,4-dihydrophthalazin-1-yl) phenyl]pyrazolo[1,5-a] pyridine-3-carboxamide486.1 A: 5.99 B: 5.45 ¹H NMR (500 MHz, DMSO-d₆) d 12.81 (s, 1H), 10.04(s, 1H), 8.75 (s, 1H), 8.69 (d, J = 7.4 Hz, 1H), 8.36-8.33 (m, 1H),8.01-7.86 (m, 4H), 7.78 (dd, J = 7.7, 0.8 Hz, 1H), 7.63-7.56 (m, 3H),6.81 (dd, J = 7.4, 2.8 Hz, 1H), 4.15- 4.09 (m, 1H), 4.05-3.99 (m, 2H),3.48-3.41 (m, 2H), 3.35-3.30 (m, 3H) 195

1-(3-methylphenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-imidazole- 4-carboxamide 422.1 A: 8.34 B: 7.46 ¹H NMR (500MHz, DMSO-d₆) d 12.81 (s, 1H), 10.20 (s, 1H), 8.45 (s, 1H), 8.48 (s,1H), 8.35 (d, J = 7.2 Hz, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.96-7.87 (m,2H), 7.77 (d, J = 8.0 Hz, 1H), 7.66 (s, 1H), 7.61-7.54 (m, 3H), 7.44 (s,1H), 7.26 (d, J = 7.7 Hz, 1H), 6.51 (s, 1H), 2.41 (s, 3H) 196

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-3-phenyl-4,5-dihydro-1,2-oxazole-5- carboxamide 411.2 E: 1.56 F: 1.58 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.50 (s, 1H), 8.36-8.25 (m, 1H),7.96-7.82 (m, 4H), 7.77-7.66 (m, 3H), 7.55 (d, J = 8.2 Hz, 2H),7.52-7.41 (m, 3H), 5.32 (dd, J = 10.4, 7.9 Hz, 1H), 3.79-3.68 (m, 2H)197

1-(2-methoxyphenyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 4-carboxamide 438.3 E: 1.51 F: 1.51 (500 MHz,DMSO-d₆) δ ppm 12.85 (s, 1H), 10.21 (s, 1H), 8.83 (s, 1H), 8.34 (d, J =7.1 Hz, 1H), 8.29 (s, 1H), 7.97- 7.85 (m, 4H), 7.76 (d, J = 7.7 Hz, 1H),7.67 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.47-7.39 (m, 1H),7.30 (d, J = 8.4 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 3.91 (s, 3H) 198

1-(3-chlorophenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 4-carboxamide 442.2 E: 1.75 F: 1.75 (500 MHz,DMSO-d₆) δ ppm 12.85 (s, 1H), 10.24 (s, 1H), 9.20 (s, 1H), 8.39 (s, 1H),8.34 (d, J = 7.4 Hz, 1H), 8.01 (br. s., 1H), 7.96-7.87 (m, 5H), 7.77 (d,J = 7.4 Hz, 1H), 7.63- 7.55 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H) 199

5-chloro-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-4-carboxamide 442.2 E: 1.62 F: 1.62 (500 MHz, DMSO-d₆) δ ppm12.85 (s, 1H), 10.31 (s, 1H), 8.47 (s, 1H), 8.35 (d, J = 7.1 Hz, 1H),7.98-7.84 (m, 4H), 7.76 (d, J = 7.4 Hz, 1H), 7.67-7.54 (m, 7H) 200

1-benzyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-4-carboxamide 422.2 E: 1.44 F: 1.44 (500 MHz, DMSO-d₆) δ ppm 12.83 (s,1H), 10.07 (s, 1H), 8.48 (s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 8.10 (s,1H), 7.97- 7.84 (m, 4H), 7.75 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.4 Hz,2H), 7.42-7.35 (m, 2H), 7.34-7.27 (m, 3H), 5.40 (s, 2H) 201

5-(adamantan-1-yl)-1- methyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 3-carboxamide 480.3 E: 2.20 F: 2.21 (500 MHz,DMSO-d₆) δ ppm 12.83 (s, 1H), 10.16 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H),7.97 (d, J = 8.4 Hz, 2H), 7.94-7.85 (m, 2H), 7.75 (d, J = 7.4 Hz, 1H),7.55 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 4.08 (s, 3H), 2.06 (br. s., 3H),2.00 (br. s., 6H), 1.84-1.65 (m, 6H) 202

1-(3-chloro-2- fluorophenyl)-5-methyl- N-[4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-pyrazole- 4-carboxamide 474.2 E: 1.72F: 1.72 (500 MHz, DMSO-d₆) δ ppm 12.84 (s, 1H), 10.15 (s, 1H), 8.42 (s,1H), 8.34 (d, J = 7.1 Hz, 1H), 7.98-7.87 (m, 4H), 7.84 (t, J = 7.1 Hz,1H), 7.76 (d, J = 7.4 Hz, 1H), 7.64 (t, J = 6.9 Hz, 1H), 7.58 (d, J =8.1 Hz, 2H), 7.46 (t, J = 7.9 Hz, 1H), 2.45 (s, 3H) 203

1-(3-methoxyphenyl)-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 4-carboxamide 438.2 E: 1.56 F: 1.64 (500 MHz,DMSO-d₆) δ ppm 10.31 (s, 1H), 8.69 (d, J = 2.5 Hz, 1H), 8.39-8.32 (m,1H), 7.98-7.88 (m, 5H), 7.83 (dd, J = 4.8, 3.4 Hz, 2H), 7.77 (d, J = 7.4Hz, 1H), 7.66 (d, J = 1.7 Hz, 1H), 7.62-7.56 (m, 2H), 6.64-6.59 (m, 1H),4.05 (s, 3H) 204

1-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-4-carboxamide 360.2 E: 1.34 F: 1.36 (500 MHz, DMSO-d₆) δ ppm 12.82 (s,1H), 10.17 (s, 1H), 8.35-8.31 (m, 1H), 7.97 (d, J = 8.5 Hz, 2H),7.94-7.86 (m, 3H), 7.74 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H),6.80 (d, J = 2.4 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.3 Hz,3H) 205

1,5-dimethyl-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 3-carboxamide 360.2 E: 1.30 F: 1.32 (500 MHz,DMSO-d₆) δ ppm 12.81 (s, 1H), 10.12 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H),7.96 (d, J = 8.2 Hz, 2H), 7.90 (quin, J = 6.9 Hz, 2H), 7.74 (d, J = 7.6Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 6.59 (s, 1H), 3.84 (s, 3H), 2.31 (s,3H) 206

5-tert-butyl-1-methyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 3-carboxamide 402.2 E: 1.68 F: 1.72 (500 MHz,DMSO-d₆) δ ppm 12.82 (s, 1H), 10.12 (s, 1H), 8.33 (d, J = 7.0 Hz, 1H),7.99-7.85 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H),6.59 (s, 1H), 4.03 (s, 3H), 1.36 (s, 9H) 207

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-5-phenyl-1H-pyrazole-3-carboxamide 422.2 E: 1.70 F: 1.75 (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 10.31 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.5Hz, 2H), 7.94-7.85 (m, 2H), 7.75 (d, J = 7.6 Hz, 1H), 7.64-7.58 (m, 2H),7.58- 7.51 (m, 4H), 7.52-7.44 (m, 1H), 6.95 (s, 1H), 3.97 (s, 3H) 208

1-benzyl-5-methyl-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 3-carboxamide 436.2 E: 1.73 F: 1.76 (500 MHz,DMSO-d₆) δ ppm 12.82 (s, 1H), 10.18 (s, 1H), 8.36-8.31 (m, 1H), 7.97 (d,J = 8.5 Hz, 2H), 7.94-7.85 (m, 2H), 7.74 (d, J = 7.3 Hz, 1H), 7.54 (d, J= 8.5 Hz, 2H), 7.40-7.33 (m, 2H), 7.32-7.25 (m, 1H), 7.17 (d, J = 7.3Hz, 2H), 6.67 (s, 1H), 5.44 (s, 2H), 2.25 (s, 3H) 209

1-(3-methylphenyl)-2- oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrrolidine-3- carboxamide 439.2 E: 1.63 F: 1.66 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.52 (s, 1H), 8.47-8.30 (m, 1H),7.94-7.86 (m, 2H), 7.83-7.78 (m, J = 8.2 Hz, 2H), 7.72 (d, J = 7.3 Hz,1H), 7.59-7.52 (m, J = 8.5 Hz, 2H), 7.49-7.43 (m, 2H), 7.27 (t, J = 7.8Hz, 1H), 6.99 (d, J = 7.3 Hz, 1H), 3.95-3.86 (m, 2H), 3.80 (t, J = 8.7Hz, 1H), 2.48-2.35 (m, 2H), 2.31 (s, 3H) 210

1-(4-methylphenyl)-5- oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrrolidine-3- carboxamide 439.2 E: 1.49 F: 1.50 ¹H NMR (500MHz, DMSO-d₆) d 12.81 (s, 1H), 10.44 (s, 1H), 8.43-8.25 (m, 1H),7.95-7.84 (m, 2H), 7.80-7.74 (m, J = 8.2 Hz, 2H), 7.70 (d, J = 7.0 Hz,1H), 7.53 (t, J = 8.4 Hz, 4H), 7.24-7.15 (m, J = 8.2 Hz, 2H), 4.09 (t, J= 9.3 Hz, 1H), 3.98 (dd, J = 9.8, 6.1 Hz, 1H), 2.89-2.68 (m, 3H), 2.27(s, 3H) 211

1-(3-chloro-2- fluorophenyl)-5-oxo-N- [4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]pyrrolidine-3- carboxamide 477.2 E: 1.48F: 1.49 ¹H NMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.44 (s, 1H),8.40-8.26 (m, 1H), 7.94-7.86 (m, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.70 (d,J = 7.3 Hz, 1H), 7.59-7.51 (m, 3H), 7.46 (t, J = 6.9 Hz, 1H), 7.28 (t, J= 8.4 Hz, 2H), 4.12- 4.03 (m, 1H), 4.00-3.91 (m, 1H), 2.85-2.63 (m, 3H)212

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-4-carboxamide 346.2 E: 1.09 F: 1.10 (500 MHz, DMSO-d₆) δ ppm 12.82 (s,1H), 10.06 (s, 1H), 8.35-8.32 (m, 1H), 8.31 (s, 1H), 8.04 (s, 1H),7.93-7.83 (m, 4H), 7.74 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H),3.89 (s, 3H) 213

5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-3-carboxamide 422.2 E: 1.73 F: 1.77 (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 10.24 (s, 1H), 8.35-8.29 (m, 1H), 7.96 (d, J = 8.5 Hz,2H), 7.94-7.83 (m, 2H), 7.74 (d, J = 7.3 Hz, 1H), 7.65-7.61 (m, 2H),7.60- 7.54 (m, 4H), 7.53-7.48 (m, 1H), 6.82 (s, 1H), 2.35 (s, 3H) 214

5-methyl-1-(2- methylphenyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 4-carboxamide 436.2 E: 1.64 F: 1.67 (500 MHz,DMSO-d₆) δ ppm 12.83 (s, 1H), 10.09 (s, 1H), 8.38-8.31 (m, 2H),7.98-7.84 (m, 4H), 7.75 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H),7.49-7.42 (m, 2H), 7.39 (t, J = 6.9 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H),3.61 (s, 3H), 2.31 (s, 3H) 215

2-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenylpyrrolidine-3- carboxamide 425.1 E: 1.50 F: 1.52 ¹H NMR (500 MHz,DMSO-d₆) d 12.82 (s, 1H), 10.53 (s, 1H), 8.35-8.30 (m, 1H), 7.94-7.86(m, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 7.0 Hz, 1H), 7.69-7.62(m, J = 7.9 Hz, 2H), 7.59-7.52 (m, J = 8.5 Hz, 2H), 7.40 (t, J = 7.9 Hz,2H), 7.17 (t, J = 7.3 Hz, 1H), 4.01-3.88 (m, 2H), 3.84-3.77 (m, 1H),2.48-2.32 (m, 2H) 216

1-(2-methoxyphenyl)-2- oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]pyrrolidine-3- carboxamide 455.1 E: 1.43 F: 1.45 ¹H NMR (500MHz, DMSO-d₆) d 12.82 (s, 1H), 10.48 (s, 1H), 8.45-8.25 (m, 1H),7.93-7.86 (m, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.74-7.70 (m, 1H), 7.55 (d,J = 8.5 Hz, 2H), 7.36-7.29 (m, 1H), 7.22 (dd, J = 7.6, 1.2 Hz, 1H), 7.11(d, J = 8.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 3.79 (s, 3H), 3.73-3.67(m, 2H), 2.41-2.31 (m, 1H) 217

5-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenylpyrrolidine-3- carboxamide 425 E: 1.93 F: 1.97 ¹H NMR (500 MHz,DMSO-d₆) d 12.82 (s, 1H), 10.46 (s, 1H), 8.33 (d, J = 7.6 Hz, 1H),7.93-7.86 (m, 2H), 7.78 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 7.3 Hz, 1H),7.68-7.62 (m, J = 8.6 Hz, 2H), 7.57-7.51 (m, J = 8.2 Hz, 2H), 7.38 (t, J= 7.6 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 4.13 (t, J = 9.2 Hz, 1H), 4.01(dd, J = 9.8, 5.8 Hz, 1H), 2.95-2.82 (m, 2H), 2.82-2.75 (m, 1H) 218

5-oxo-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(propan-2-yl)pyrrolidine-3- carboxamide 391.1 E: 1.63 F: 1.66 ¹H NMR (500 MHz,DMSO-d₆) d 10.35 (s, 1H), 8.41- 8.26 (m, 1H), 8.02-7.82 (m, 2H),7.80-7.66 (m, 3H), 7.53 (d, J = 8.5 Hz, 2H), 4.14 (dt, J = 13.7, 6.8 Hz,1H), 3.62 (s, 2H), 3.43 (dd, J = 9.8, 6.1 Hz, 1H), 3.32 (t, J = 7.2 Hz,1H), 2.62-2.53 (m, 1H), 1.07 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 7.0 Hz,3H) 219

3,5-dimethyl-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1-phenyl-1H- pyrazole-4-carboxamide 436.3 E: 1.44 F: 1.53(500 MHz, DMSO-d₆) δ ppm 12.83 (s, 1H), 10.08 (s, 1H), 8.34 (d, J = 6.7Hz, 1H), 7.96-7.89 (m, 2H), 7.89-7.83 (m, 2H), 7.87 (d, J = 8.4 Hz, 2H),7.76 (d, J = 7.1 Hz, 1H), 7.61-7.53 (m, 3H), 7.53-7.43 (m, 2H), 2.43 (s,3H), 2.38 (s, 3H) 220

1-(2-chlorophenyl)-N-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 4-carboxamide 442.1 E: 1.59 F: 1.61 (500 MHz,DMSO-d₆) δ ppm 12.82 (s, 1H), 10.19 (s, 1H), 8.81 (s, 1H), 8.38-8.32 (m,2H), 7.95-7.91 (m, 3H), 7.90- 7.87 (m, 1H), 7.80-7.73 (m, 2H), 7.71-7.67(m, 1H), 7.60 (d, J = 8.5 Hz, 2H), 7.58-7.54 (m, 2H) 221

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-(propan-2-yl)-1H-1,2,3- triazole-4-carboxamide 451.3 E: 1.84 F: 1.84 ¹HNMR (500 MHz, DMSO-d₆) d 12.85 (s, 1H), 10.76 (s, 1H), 8.35 (d, J = 7.4Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.98- 7.85 (m, 2H), 7.76 (d, J = 7.7Hz, 1H), 7.69 (d, J = 3.7 Hz, 3H), 7.59 (d, J = 8.1 Hz, 4H), 3.26-3.18(m, 1H), 1.33 (d, J = 7.1 Hz, 6H) 222

1-(2-fluorophenyl)-5- methyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-1,2,3- triazole-4-carboxamide 441.2 E: 1.66 F: 1.66 ¹H NMR(500 MHz, DMSO-d₆) d 12.84 (s, 1H), 10.80 (s, 1H), 8.34 (d, J = 7.4 Hz,1H), 8.11-8.02 (m, J = 8.4 Hz, 2H), 7.98-7.87 (m, 2H), 7.83-7.72 (m,3H), 7.64 (t, J = 9.1 Hz, 1H), 7.60-7.56 (m, J = 8.4 Hz, 2H), 7.52 (t, J= 7.6 Hz, 1H), 3.46-3.34 (m, 1H) 223

5-[4-(2-hydroxypropan-2- yl)phenyl]-3-methyl-N- [4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1,2-oxazole-4- carboxamide 481.2 E: 1.47F: 1.42 ¹H NMR (500 MHz, DMSO-d₆) d 8.35 (d, J = 6.7 Hz, 1H), 7.91 (t, J= 5.7 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.81-7.72 (m, 3H), 7.61 (d, J =8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 3H), 2.39 (s, 3H), 1.43 (s, 6H) 224

5-[4-(hydroxymethyl) phenyl]-3-methyl-N-[4- (4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1,2-oxazole-4- carboxamide 453.2 E: 1.33F: 1.36 ¹H NMR (500 MHz, DMSO-d₆) d 10.76 (s, 1H), 8.40- 8.30 (m, 1H),7.95-7.88 (m, 2H), 7.86-7.73 (m, 5H), 7.60 (d, J = 8.5 Hz, 2H), 7.50 (d,J = 8.3 Hz, 2H), 5.33 (br. s., 1H), 4.56 (d, J = 4.4 Hz, 2H), 2.40 (s,3H) 225

1-(3-chlorophenyl)-5- ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-1,2,3- triazole-4-carboxamide 470.3 E: 1.61 F: 1.61 ¹H NMR(500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.79 (s, 1H), 8.35 (d, J = 7.6 Hz,1H), 8.11-8.04 (m, J = 8.2 Hz, 2H), 7.96-7.85 (m, 3H), 7.79-7.69 (m,3H), 7.68-7.64 (m, 1H), 7.61-7.55 (m, J = 8.5 Hz, 2H), 3.03 (q, J = 7.3Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H) 226

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-3-carboxamide 408.1 E: 1.58 F: 1.67 (500 MHz, DMSO-d₆) δ ppm12.85 (s, 1H), 10.38 (s, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.35 (d, J = 7.7Hz, 1H), 8.04 (dd, J = 8.1, 4.4 Hz, 4H), 7.97-7.86 (m, 2H), 7.77 (d, J =7.7 Hz, 1H), 7.64-7.52 (m, 4H), 7.42 (t, J = 7.4 Hz, 1H), 7.08 (d, J =2.4 Hz, 1H) 227

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-pyrazole-3-carboxamide 346.1 E: 1.07 F: 1.07 (500 MHz, DMSO-d₆) δ ppm 12.83 (s,1H), 10.27 (s, 1H), 8.34 (d, J = 7.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H),7.96-7.83 (m, 3H), 7.75 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H),6.80 (d, J = 2.0 Hz, 1H), 3.98 (s, 3H) 228

3-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-4-carboxamide 422.2 E: 1.66 F: 1.66 (500 MHz, DMSO-d₆) δ ppm12.84 (s, 1H), 10.09 (s, 1H), 9.11 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H),7.97-7.86 (m, 4H), 7.82 (d, J = 8.1 Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H),7.61-7.51 (m, 4H), 7.41-7.33 (m, 1H) 229

1-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-5-propyl-1H-pyrazole-3-carboxamide 388.1 E: 1.49 F: 1.49 (500 MHz, DMSO-d₆) δ ppm12.82 (s, 1H), 10.18 (s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 7.99 (d, J = 8.4Hz, 2H), 7.95-7.84 (m, 2H), 7.75 (d, J = 7.1 Hz, 1H), 7.54 (d, J = 8.4Hz, 2H), 6.60 (s, 1H), 3.87 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.65(sxt, J = 7.4 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H) 230

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-2-phenyl-1H-imidazole-4-carboxamide 408.2 E: 1.23 F: 1.49 ¹H NMR (500 MHz, DMSO-d₆)d 12.82 (s, 1H), 10.05 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.14-8.06 (m,J = 7.6 Hz, 2H), 8.04-7.97 (m, 3H), 7.96-7.87 (m, 2H), 7.77 (d, J = 7.9Hz, 1H), 7.61-7.54 (m, J = 8.2 Hz, 2H), 7.52 (t, J = 7.5 Hz, 2H), 7.44(t, J = 7.3 Hz, 1H) 231

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-5-propyl-1H-1,2,3-triazole- 4-carboxamide 451.1 E: 1.93 F: 1.95 ¹H NMR(500 MHz, DMSO-d₆) d 12.83 (s, 1H), 10.73 (s, 1H), 8.35 (d, J = 7.0 Hz,1H), 8.10-8.00 (m, J = 8.2 Hz, 2H), 7.96-7.86 (m, 2H), 7.76 (d, J = 7.9Hz, 1H), 7.71- 7.65 (m, 3H), 7.64-7.61 (m, 2H), 7.60-7.54 (m, J = 8.5Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H), 1.54-1.42 (m, 2H), 0.76 (t, J = 7.3Hz, 3H) 232

5-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-[3-(trifluoromethyl)phenyl]- 1H-1,2,3-triazole-4- carboxamide 491.1 E: 1.92F: 1.91 ¹H NMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 10.79 (s, 1H),8.39-8.33 (m, 1H), 8.14 (s, 1H), 8.10-8.02 (m, 4H), 7.96-7.87 (m, 3H),7.80-7.73 (m, 1H), 7.59 (d, J = 8.5 Hz, 2H) 233

1-ethyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1H-imidazole-5-carboxamide 360.2 E: 1.04 F: 1.18 ¹H NMR (500 MHz, DMSO-d₆) d 12.82(s, 1H), 10.27 (s, 1H), 8.34 (d, J = 7.3 Hz, 1H), 7.99-7.83 (m, 6H),7.74 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 4.36 (q, J = 6.9 Hz,2H), 1.34 (t, J = 7.2 Hz, 3H) 234

N-(1-tert-butyl-3-{[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]carbamoyl}- 1H-pyrazol-4-yl)pyridine- 4-carboxamide 508.2 E:1.41 F: 1.71 1H-NMR: (500 MHz, DMSO-d₆) δ ppm 12.87 (s, 1H), 10.59 (s,1H), 10.28 (s, 1H), 8.81 (d, J = 5.4 Hz, 2H), 8.44 (s, 1H), 8.34 (d, J =8.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.95-7.86 (m, 2H), 7.80 (d, J =5.7 Hz, 2H), 7.74 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 1.63(s, 9H) 235

1-tert-butyl-5-methyl-N- [4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrazole- 3-carboxamide 402.2 E: 1.67 F: 1.68 1H-NMR: (500MHz, DMSO-d₆) δ ppm 12.84 (s, 1H), 9.86 (s, 1H), 7.98-7.85 (m, 4H), 7.75(d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.4 Hz, 2H), 6.61 (s, 1H), 2.47 (s,3H), 1.63 (s, 9H) 236

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-phenyl-1H-pyrazole-5-carboxamide 408.2 E: 1.48 F: 1.44 1H-NMR: (500 MHz, DMSO-d₆)δ ppm 12.85 (s, 1H), 10.81 (s, 1H), 8.40-8.25 (m, 1H), 7.94-7.85 (m,2H), 7.83-7.76 (m, 3H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz,2H), 7.50-7.36 (m, 5H), 7.07 (s, 1H) 237

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-5-(pyridin-2-yl)-1H-1,2,4-triazole-3- carboxamide 410.2 E: 1.01 F: 1.11 ¹H NMR (500MHz, DMSO-d₆) d 12.86 (s, 1H), 8.78 (d, J = 4.0 Hz, 1H), 8.36 (d, J =7.1 Hz, 1H), 8.24 (d, J = 8.1 Hz, 1H), 8.12-8.03 (m, 3H), 7.97-7.88 (m,2H), 7.78 (d, J = 7.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 3H) 238

2-(2,3-dichlorophenyl)-5- methyl-N-[4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-2H-1,2,3- triazole-4-carboxamide 491.2 E: 2.07 F: 1.97 ¹H NMR(500 MHz, DMSO-d₆) d 10.72 (s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 8.02-7.97(m, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.93-7.88 (m, 2H), 7.84(d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.1 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H),7.60- 7.56 (m, J = 8.8 Hz, 2H), 3.89 (s, 1H), 2.64-2.57 (m, 3H) 239

1-(2-cyano-5- methoxyphenyl)-N-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-1,2,4- triazole-3-carboxamide 464.2 E: 1.38 F: 1.30 ¹H NMR(500 MHz, DMSO-d₆) d 9.39 (s, 1H), 8.34 (d, J = 7.1 Hz, 1H), 8.03 (d, J= 8.4 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.97-7.88 (m, 2H), 7.75 (d, J =7.4 Hz, 1H), 7.64- 7.55 (m, 3H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 3.95(s, 3H) 240

N-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-1-(pyridin-2-yl)-1H-1,2,4-triazole-3- carboxamide 410.3 E: 1.08 F: 1.10 ¹H NMR (500MHz, DMSO-d₆) d 12.85 (s, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.35 (d, J =7.1 Hz, 1H), 8.23 (d, J = 7.7 Hz, 1H), 8.05 (d, J = 8.8 Hz, 3H),7.97-7.87 (m, 2H), 7.77 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 3H),3.90 (s, 1H) 241

4-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-2-(1,2,3,4-tetrahydroquinolin-1-yl)- 1,3-thiazole-5- carboxamide 494.1 E: 1.85 F:2.00 ¹H NMR (500 MHz, DMSO-d₆) d 12.80 (br. s., 1H), 9.89 (br. s., 1H),8.38-8.30 (m, 1H), 7.95-7.88 (m, 3H), 7.84- 7.79 (m, J = 8.5 Hz, 2H),7.76-7.71 (m, 1H), 7.60-7.51 (m, J = 8.5 Hz, 2H), 7.30-7.20 (m, 2H),7.13-7.06 (m, 1H), 3.98-3.88 (m, 2H), 2.79 (t, J = 6.3 Hz, 2H), 2.54 (s,3H), 1.96 (quin, J = 6.2 Hz, 2H) 242

2-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1H-imidazole-4-carboxamide 346.2 E: 1.07 F: 0.92 ¹H NMR (500 MHz, DMSO-d₆) d 12.80(s, 1H), 10.00 (br. s., 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.03-7.97 (m, J =8.2 Hz, 2H), 7.94-7.86 (m, 2H), 7.78-7.73 (m, 2H), 7.58- 7.49 (m, J =8.2 Hz, 2H), 2.38 (s, 3H) 243

4-methyl-N-[4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-2-(phenylamino)-1,3- thiazole-5-carboxamide 454.2 E: 1.85 F: 2.00 ¹H NMR(500 MHz, DMSO-d₆) d 9.93 (s, 1H), 8.34 (d, J = 7.9 Hz, 1H), 7.99-7.88(m, 3H), 7.82 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 7.9 Hz, 1H), 7.64-7.60(m, J = 8.2 Hz, 2H), 7.58-7.53 (m, J = 8.2 Hz, 2H), 7.35 (t, J = 7.6 Hz,2H), 7.25 (br. s., 2H), 7.15 (br. s., 2H), 7.05 (br. s., 2H), 2.06 (s,3H)

Example 244:3-(Dimethylamino)-N-[4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl]benzamide,TFA

Intermediate 66 (15 mg, 0.043 mmol), 3-(dimethylamino)benzoic acid (14mg, 0.086 mmol), and HATU (24 mg, 0.064 mmol) were dissolved in DMF (1mL). DIEA (0.037 mL, 0.21 mmol) was added, then the mixture was stirredat rt for 24 h. The mixture was concentrated, then was purified by prepHPLC to afford Example 244 (9 mg, 41% yield). MS(ESI) m/z: 384.1 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 11.43 (d, J=5.8 Hz, 1H), 10.24 (s, 1H), 8.30(dd, J=8.0, 0.8 Hz, 1H), 7.97-7.86 (m, 2H), 7.77-7.68 (m, 1H), 7.60-7.52(m, 2H), 7.49-7.39 (m, 2H), 7.36-7.31 (m, 1H), 7.29-7.20 (m, 2H), 7.09(d, J=5.8 Hz, 1H), 6.99-6.91 (m, 1H), 2.98 (s, 6H); HPLC RT=5.63 min(Method A), 5.22 min (Method B).

Example 245:4-(Dimethylamino)-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzamide,formate salt

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (15 mg, 0.043 mmol) and 4-(dimethylamino)benzoic acid(14.15 mg, 0.086 mmol) afforded Example 245 (2.1 mg, 11% yield). MS(ESI)m/z: 384.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.42 (d, J=4.4 Hz, 1H),9.98 (s, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.89 (d, J=8.5 Hz, 4H), 7.71 (t,J=7.6 Hz, 1H), 7.59-7.49 (m, 2H), 7.38 (d, J=7.7 Hz, 2H), 7.08 (d, J=5.0Hz, 1H), 6.78 (d, J=8.0 Hz, 2H), 3.01 (s, 6H); HPLC RT=1.51 min (MethodE), 1.71 min (Method F).

Example 246:N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (15 mg, 0.043 mmol) and4,5,6,7-tetrahydrobenzo[d]thiazole-2-carboxylic acid (12 mg, 0.064 mmol)afforded Example 246 (7.9 mg, 46% yield). MS(ESI) m/z: 402.1 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 11.51 (br. s., 1H), 10.86 (br. s., 1H), 8.29(d, J=7.2 Hz, 1H), 8.02-7.94 (m, 2H), 7.71 (br. s., 1H), 7.58-7.51 (m,2H), 7.47-7.37 (m, J=7.7 Hz, 2H), 7.10 (br. s., 1H), 2.95-2.81 (m, 4H),1.85 (br. s., 4H); HPLC RT=2.02 min (Method E), 2.02 min (Method F).

Example 247:N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzo[c]isoxazole-3-carboxamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (15 mg, 0.043 mmol) andbenzo[c]isoxazole-3-carboxylic acid (10.5 mg, 0.064 mmol) affordedExample 247 (4 mg, 19% yield). MS(ESI) m/z: 382.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.46 (br. s., 1H), 11.25 (br. s., 1H), 8.31 (d, J=8.0Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.00 (d, J=6.9 Hz, 2H), 7.83 (d, J=9.1Hz, 1H), 7.72 (br. s., 1H), 7.56 (d, J=7.2 Hz, 3H), 7.47 (d, J=6.9 Hz,2H), 7.39-7.31 (m, 1H), 7.13 (d, J=5.5 Hz, 1H); HPLC RT=8.83 min (MethodA), 7.54 min (Method B).

Example 248:1-Methyl-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-1H-indole-2-carboxamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (15 mg, 0.043 mmol) and1-methyl-1H-indole-2-carboxylic acid (11.3 mg, 0.064 mmol) affordedExample 248 (1.4 mg, 8% yield). MS(ESI) m/z: 394.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 11.44 (br. s., 1H), 10.44 (br. s., 1H), 8.31 (d, J=7.7Hz, 1H), 7.92-7.88 (m, J=7.7 Hz, 2H), 7.71 (br. s., 2H), 7.64-7.51 (m,3H), 7.48-7.40 (m, J=7.7 Hz, 2H), 7.37-7.29 (m, 2H), 7.15 (t, J=7.0 Hz,1H), 7.10 (br. s., 1H), 4.04 (br. s., 3H); HPLC RT=1.96 min (Method E),1.94 min (Method F).

Example 249:N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4-(piperidin-1-yl)benzamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (15 mg, 0.043 mmol) and 4-(piperidin-1-yl)benzoicacid (12 mg, 0.059 mmol) afforded Example 249 (4.8 mg, 26% yield).MS(ESI) m/z: 424.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.43 (br. s.,1H), 10.03 (br. s., 1H), 8.30 (d, J=7.7 Hz, 1H), 7.93-7.85 (m, 4H),7.75-7.67 (m, 1H), 7.58-7.49 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.08 (s,1H), 7.00 (d, J=8.3 Hz, 2H), 1.60 (br. s., 6H); HPLC RT=1.39 min (MethodE), 1.97 min (Method F).

Example 250:4-Morpholino-N-(4-(1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)benzamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (13 mg, 0.037 mmol) and 4-morpholinobenzoic acid(11.54 mg, 0.056 mmol) afforded Example 250 (3.7 mg, 22% yield). MS(ESI)m/z: 422.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.41 (br. s., 1H), 10.08(br. s., 1H), 8.30 (d, J=8.0 Hz, 1H), 8.02-7.86 (m, 4H), 7.71 (t, J=7.4Hz, 1H), 7.60-7.52 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.11-7.02 (m, 3H),3.76 (br. s., 4H), 3.27 (br. s., 4H); HPLC RT=1.51 min (Method E), 1.51min (Method F).

Example 251:N-(4-(1-Oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-4-(pyrrolidin-1-yl)benzamide

According to the procedure for the preparation of Example 244, couplingof Intermediate 66 (13 mg, 0.037 mmol) and 4-(pyrrolidin-1-yl)benzoicacid (10.65 mg, 0.056 mmol) afforded Example 251 (0.4 mg, 3% yield).MS(ESI) m/z: 410.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.95 (br. s.,1H), 8.30 (d, J=7.7 Hz, 1H), 7.89 (d, J=7.7 Hz, 4H), 7.76-7.67 (m, 1H),7.59-7.51 (m, 2H), 7.37 (d, J=8.0 Hz, 2H), 7.08 (s, 1H), 6.61 (d, J=8.3Hz, 2H), 3.90 (s, 1H), 1.99 (br. s., 4H); HPLC RT=1.92 min (Method E),1.91 min (Method F).

Example 252:4-(4-(2-(5-Methoxy-7-methylindolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

Intermediate 1 (15 mg, 0.038 mmol), 5-methoxy-7-methylindoline (9.3 mg,0.057 mmol), and HATU (21.8 mg, 0.057 mmol) were dissolved in DMF (1mL). The this mixture was added DIEA (0.017 mL, 0.095 mmol). The mixturewas stirred at rt overnight, then was concentrated. The residue waspurified by prep HPLC to afford Example 252 (11 mg, 65% yield). MS(ESI)m/z: 426.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.34 (d,J=6.9 Hz, 1H), 7.98-7.85 (m, 2H), 7.71 (d, J=6.6 Hz, 1H), 7.63-7.54 (m,J=7.4 Hz, 2H), 7.50-7.42 (m, J=7.4 Hz, 2H), 6.72 (br. s., 1H), 6.57 (br.s., 1H), 4.12 (t, J=7.0 Hz, 2H), 4.00 (br. s., 2H), 3.71 (s, 3H), 2.97(t, J=6.9 Hz, 2H), 2.13 (s, 3H); HPLC RT=1.77 min (Method E), 1.76 min(Method F).

Example 253:4-(4-(2-(7-Bromo-5-(trifluoromethoxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 252, couplingof Intermediate 1 (15 mg, 0.038 mmol) and7-bromo-5-(trifluoromethoxy)indoline, HCl (18.2 mg, 0.057 mmol) affordedExample 253 (11 mg, 54% yield). MS(ESI) m/z: 544.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.34 (d, J=6.9 Hz, 1H), 8.00-7.82 (m,2H), 7.71 (d, J=6.9 Hz, 1H), 7.61-7.53 (m, 2H), 7.51-7.43 (m, 3H), 7.40(br. s., 1H), 4.22 (t, J=7.3 Hz, 2H), 4.06 (s, 2H), 3.15 (t, J=7.2 Hz,2H); HPLC RT=2.08 min (Method E), 2.06 min (Method F).

Example 254:4-(4-(2-(6-Ethoxyindolin-1-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 252, couplingof Intermediate 67 (12 mg, 0.043 mmol) and 6-ethoxyindoline (0.430 mL,0.086 mmol) afforded Example 254 (10.5 mg, 55% yield). MS(ESI) m/z:425.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.44 (br. s., 1H), 8.30 (d,J=7.7 Hz, 1H), 7.75 (br. s., 1H), 7.73-7.66 (m, 1H), 7.54 (d, J=7.7 Hz,2H), 7.40 (s, 4H), 7.13-7.05 (m, 2H), 6.55 (d, J=8.0 Hz, 1H), 4.23 (t,J=7.8 Hz, 2H), 3.95 (q, J=6.6 Hz, 2H), 3.91 (br. s., 2H), 3.08 (t, J=8.0Hz, 2H), 1.29 (t, J=6.7 Hz, 3H); HPLC RT=1.95 min (Method E), 1.95 min(Method F).

Example 255:4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)phenyl)-6,7-dimethoxyisoquinolin-1(2H)-one

To Intermediate 68 (20 mg, 0.070 mmol), Intermediate 9 (25.6 mg, 0.070mmol) and K₃PO₄ (37.4 mg, 0.176 mmol), were added dioxane (3 mL) andwater (0.333 mL). The mixture was degassed (evacuated and flushed withAr (5×)). Pd(PPh₃)₄ (4.1 mg, 3.5 μmol) was added, then the mixture wasdegassed (2×). The reaction vial was sealed and heated in a microwavereactor at 150° C. for 25 min. The reaction mixture was concentratedthen was purified by prep HPLC to afford Example 255 (7.5 mg, 24%yield). MS(ESI) m/z: 441.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.30(br. s., 1H), 7.68 (s, 1H), 7.50-7.33 (m, 6H), 7.31 (br. s., 2H), 6.98(br. s., 2H), 4.96 (br. s., 2H), 4.69 (br. s., 2H), 3.95-3.86 (m, 3H),3.84 (br. s., 2H), 3.72 (s, 3H); HPLC RT=1.62 min (Method E), 1.62 min(Method F).

Example 256:4-(2-Fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 255, couplingof Intermediate 5 (37 mg, 0.098 mmol) and 4-bromoisoquinolin-1(2H)-one(20 mg, 0.089 mmol) afforded Example 256 (6.6 mg, 18% yield). MS(ESI)m/z: 339.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.50 (br. s., 1H), 8.28(d, J=8.0 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.37(d, J=4.4 Hz, 3H), 7.34-7.20 (m, 5H), 7.16 (br. s., 1H), 4.98 (br. s.,2H), 4.70 (br. s., 2H), 3.88 (br. s., 2H); HPLC RT=1.72 min (Method E),1.70 min (Method F).

Example 257:N-(4-(6,7-Dimethoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)-6-methoxyindoline-1-carboxamide

According to the procedure for the preparation of Example 255, couplingof Intermediate 12 (33 mg, 0.084 mmol) and Intermediate 68 (20 mg, 0.070mmol) afforded Example 257 (8.9 mg, 27% yield). MS(ESI) m/z: 472.1(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (br. s., 1H), 8.61 (br. s.,1H), 7.95 (br. s., 1H), 7.74-7.66 (m, 3H), 7.55 (br. s., 1H), 7.40 (d,J=8.0 Hz, 2H), 7.08 (d, J=7.7 Hz, 1H), 7.03-6.93 (m, 2H), 6.48 (d, J=8.0Hz, 1H), 4.17 (t, J=8.1 Hz, 2H), 3.89 (s, 3H), 3.74 (s, 3H), 3.71 (s,3H), 3.11 (t, J=8.3 Hz, 2H); HPLC RT=1.71 min (Method E), 1.70 min(Method F).

Example 258:4-(4-(2-(6-Isopropoxyindolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a solution of Intermediate 1 (12 mg, 0.043 mmol), Intermediate 69(12.5 mg, 0.043 mmol), and HATU (24.4 mg, 0.064 mmol) in DMF (1 mL), wasadd DIEA (0.037 mL, 0.21 mmol). The mixture was stirred rt for 16 h,then the mixture was purified via prep HPLC to afford Example 258 (13mg; 69% yield) as white solid. MS(ESI) m/z: 440.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.86 (br. s., 1H), 8.40-8.32 (m, 1H), 7.90 (br. s.,2H), 7.74 (br. s., 2H), 7.60-7.53 (m, 2H), 7.48-7.42 (m, 2H), 7.10 (d,J=7.2 Hz, 1H), 6.55 (d, J=7.7 Hz, 1H), 4.48 (d, J=5.2 Hz, 1H), 4.28-4.17(m, 2H), 3.96 (br. s., 2H), 3.09 (br. s., 2H), 1.23 (br. s., 6H); HPLCRT=1.93 min (Method E), 191 min (Method F).

Example 259:4-(4-(2-(Indolin-1-yl)-2-oxoethyl)-2-methylphenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and Intermediate 71(34.5 mg, 0.091 mmol), afforded 1.8 mg (5.5%) of Example 259. MS(ESI)m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (br. s., 1H), 8.33(d, J=3.3 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.87 (d, J=3.3 Hz, 2H),7.34-7.21 (m, 5H), 7.15 (br. s., 1H), 7.00 (br. s., 1H), 4.23 (t, J=7.8Hz, 2H), 3.92 (br. s., 2H), 3.19 (br. s., 2H), 2.07 (br. s., 3H); HPLCRT=1.96 min (Method E), 1.99 min (Method F).

Example 260:4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and Intermediate 70(34.5 mg, 0.091 mmol), afforded 10.4 mg (32%) of Example 260. MS(ESI)m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 8.35-8.29(m, 1H), 7.90-7.81 (m, 2H), 7.41-7.34 (m, 2H), 7.34-7.29 (m, 3H), 7.27(s, 2H), 7.24-7.20 (m, 1H), 4.98 (s, 2H), 4.70 (s, 2H), 3.84 (s, 2H),2.07 (s, 3H); HPLC RT=1.70 min (Method E), 1.73 min (Method F).

Example 261:4-(2-Fluoro-4-(2-(indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and Intermediate 72(34.8 mg, 0.091 mmol), afforded 10.6 mg (31%) of Example 261. MS(ESI)m/z: 400.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.98 (br. s., 1H),8.36-8.30 (m, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.93-7.86 (m, 2H), 7.53 (t,J=7.7 Hz, 1H), 7.47-7.41 (m, 1H), 7.36 (d, J=11.0 Hz, 1H), 7.32 (d,J=7.7 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.05-6.97(m, 1H), 4.24 (t, J=8.5 Hz, 2H), 4.01 (s, 2H), 3.20 (t, J=8.4 Hz, 2H);HPLC RT=1.81 min (Method E), 1.83 min (Method F).

Example 262:4-{4-[2-(2,3-Dihydro-1H-isoindol-2-yl)-2-oxoethyl]phenyl}-6-methoxy-1,2-dihydroisoquinolin-1-one

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (25 mg, 0.098 mmol) and Intermediate 9 (35.7 mg,0.098 mmol), afforded 14.4 mg (35%) of Example 262. MS(ESI) m/z: 411.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.30 (br. s., 1H), 8.22 (d, J=8.8Hz, 1H), 7.41 (s, 4H), 7.38-7.34 (m, 2H), 7.32-7.28 (m, 2H), 7.14 (dd,J=8.8, 2.5 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=2.5 Hz, 1H), 4.96 (s, 2H),4.69 (s, 2H), 3.84 (s, 2H), 3.75 (s, 3H); HPLC RT=1.61 min (Method E),1.62 min (Method F).

Example 263:4-(4-(2-(Isoindolin-2-yl)-2-oxoethyl)-2-methylphenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 255, couplingof Intermediate 70 (32.8 mg, 0.087 mmol) and4-bromoisoquinolin-1(2H)-one (15 mg, 0.067 mmol) afforded Example 263(2.1 mg, 8% yield). MS(ESI) m/z: 395.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆)δ 11.40 (d, J=5.8 Hz, 1H), 8.27 (dd, J=8.0, 1.1 Hz, 1H), 7.64 (ddd,J=8.3, 7.0, 1.5 Hz, 1H), 7.53-7.48 (m, 1H), 7.40-7.34 (m, 2H), 7.34-7.29(m, 2H), 7.28 (s, 1H), 7.24-7.19 (m, 1H), 7.18-7.14 (m, 1H), 7.03-6.97(m, 2H), 4.97 (s, 2H), 4.69 (s, 2H), 3.80 (s, 2H), 2.03 (s, 3H); HPLCRT=1.68 min (Method E), 1.67 min (Method F).

Example 264:4-(4-(2-(Indolin-1-yl)-2-oxoethyl)-2-methylphenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 255, couplingof Intermediate 71 (32.8 mg, 0.087 mmol) and4-bromoisoquinolin-1(2H)-one (15 mg, 0.067 mmol) afforded Example 264(1.7 mg, 6% yield). MS(ESI) m/z: 395.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆)δ 11.41 (d, J=4.4 Hz, 1H), 8.28 (dd, J=8.0, 1.1 Hz, 1H), 8.09 (d, J=8.0Hz, 1H), 7.64 (td, J=7.6, 1.5 Hz, 1H), 7.54-7.47 (m, 1H), 7.28 (s, 1H),7.25 (d, J=7.4 Hz, 1H), 7.23-7.20 (m, 1H), 7.19-7.16 (m, 1H), 7.16-7.13(m, 1H), 7.01 (d, J=7.4 Hz, 3H), 4.23 (t, J=8.7 Hz, 2H), 3.88 (s, 2H),3.18 (t, J=8.5 Hz, 2H), 2.04 (s, 3H); HPLC RT=1.81 min (Method E), 1.80min (Method F).

Example 265:4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 258, couplingof Intermediate 1 (10 mg, 0.036 mmol), Intermediate 74 (11.5 mg, 0.036mmol) afforded Example 265 (13.2 mg, 0.028 mmol, 78% yield). MS(ESI)m/z: 470.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H), 8.39-8.30(m, 1H), 7.93-7.88 (m, 2H), 7.76 (d, J=2.5 Hz, 1H), 7.73-7.68 (m, 1H),7.60-7.54 (m, J=8.3 Hz, 2H), 7.50-7.43 (m, J=8.3 Hz, 2H), 7.11 (d, J=8.3Hz, 1H), 6.57 (dd, J=8.3, 2.5 Hz, 1H), 4.61 (s, 1H), 4.24 (t, J=8.5 Hz,2H), 3.96 (s, 2H), 3.63 (s, 2H), 3.10 (t, J=8.4 Hz, 2H), 1.18 (s, 6H);HPLC RT=1.61 min (Method E), 1.61 min (Method F).

Example 266:N-(4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (18 mg, 0.071 mmol) and Intermediate 10 (28.4 mg,0.078 mmol) afforded 5.3 mg (17%) of Example 266. MS(ESI) m/z: 412.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.28 (d, J=6.1 Hz, 1H), 8.64 (s,1H), 8.22 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.70-7.65 (m, 2H),7.41-7.35 (m, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.17-7.11 (m, 2H), 7.05 (d,J=6.1 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.93-6.88 (m, 1H), 4.16 (t, J=8.8Hz, 2H), 3.77 (s, 3H), 3.19 (t, J=8.5 Hz, 2H); HPLC RT=1.71 min (MethodE), 1.71 min (Method F).

Example 267: 4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl5-methoxyisoindoline-2-carboxylate

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (18 mg, 0.071 mmol) and Example 70B (28 mg, 0.071mmol) afforded 11.9 mg (36%) of Example 267. MS(ESI) m/z: 443.2 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 11.33 (br. s., 1H), 8.23 (d, J=8.8 Hz, 1H),7.54-7.44 (m, 2H), 7.35-7.26 (m, 3H), 7.15 (dd, J=8.8, 2.5 Hz, 1H),7.14-7.08 (m, 1H), 6.98 (s, 1H), 6.94-6.86 (m, 2H), 4.89 (s, 1H), 4.85(s, 1H), 4.71 (s, 1H), 4.66 (s, 1H), 3.77 (d, J=2.2 Hz, 6H); HPLCRT=1.86 min (Method E), 1.86 min (Method F).

Example 268:6-Methoxy-N-(4-(6-methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (25 mg, 0.098 mmol) and Intermediate 12 (42.7 mg,0.108 mmol) afforded 3.9 mg (9%) of Example 268. MS(ESI) m/z: 442.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.22 (d, J=8.8 Hz,1H), 7.74-7.65 (m, J=8.8 Hz, 2H), 7.55 (d, J=2.5 Hz, 1H), 7.42-7.34 (m,J=8.5 Hz, 2H), 7.14 (dd, J=8.8, 2.5 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H),7.04 (d, J=6.1 Hz, 1H), 6.94 (d, J=2.5 Hz, 1H), 6.48 (dd, J=8.3, 2.5 Hz,1H), 4.17 (t, J=8.5 Hz, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.11 (t, J=8.5Hz, 2H); HPLC RT=1.71 min (Method E), 1.71 min (Method F).

Example 269: 4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)phenylisoindoline-2-carboxylate

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (18 mg, 0.071 mmol) and Example 68B (25.9 mg, 0.071mmol) afforded 7.1 mg (23%) of Example 269. MS(ESI) m/z: 413.2 (M+H)⁺;¹H NMR (500 MHz, DMSO-d₆) δ 11.34 (d, J=5.5 Hz, 1H), 8.23 (d, J=9.1 Hz,1H), 7.53-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.36-7.33 (m, 3H), 7.16 (dd,J=8.8, 2.5 Hz, 1H), 7.10 (d, J=5.8 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H), 4.94(s, 2H), 4.75 (s, 2H), 3.77 (s, 3H); HPLC RT=1.88 min (Method E), 1.88min (Method F).

The following Examples in Table 4 were made by using the same procedureas shown in Example 3. Intermediate 1 was coupled with the appropriateamine. Various coupling reagents could be used other than the onedescribed in Example 3 such as BOP, PyBop, EDC/HOBt or HATU.

TABLE 4 LC HPLC MS Method, Ex- (M + RT ample R IUPAC name H)⁺ (min.) ¹HNMR 270

4-(4-{2-oxo-2-[6- (pyridin-3- ylmethoxy)-2,3- dihydro-1H-indol-1-yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 489.2 E: 1.33 F: 1.65 ¹HNMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.77 (s, 1H), 8.65 (d, J = 4.4Hz, 1H), 8.38-8.31 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.92-7.82 (m, 3H),7.75-7.69 (m, 1H), 7.64 (dd, J = 7.7, 5.2 Hz, 1H), 7.59-7.54 (m, J = 8.3Hz, 2H), 7.50-7.43 (m, J = 8.0 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.69(dd, J = 8.3, 2.5 Hz, 1H), 5.17 (s, 2H), 4.25 (t, J = 8.4 Hz, 2H), 3.11(t, J = 8.4 Hz, 2H) 271

4-(4-{2-oxo-2-[6- (pyridin-2- ylmethoxy)-2,3- dihydro-1H-indol-1-yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 489.2 E: 1.33 F: 1.70 ¹HNMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.57 (d, J = 4.7 Hz, 1H),8.40-8.28 (m, 1H), 7.98-7.82 (m, 4H), 7.73 (d, J = 8.0 Hz, 1H), 7.56 (d,J = 8.0 Hz, 2H), 7.50-7.44 (m, 2H), 7.38-7.31 (m, 1H), 7.13 (d, J = 8.0Hz, 1H), 6.66 (dd, J = 8.1, 2.1 Hz, 1H), 5.13 (s, 2H), 4.24 (t, J = 8.4Hz, 2H), 3.96 (s, 2H), 3.10 (t, J = 8.3 Hz, 2H) 272

4-(4-{2-oxo-2-[6- (pyridin-2- ylmethoxy)-2,3- dihydro-1H-indol-1-yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 489.2 E: 1.30 F: 1.64 ¹HNMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.55 (d, J = 5.8 Hz, 2H),8.39-8.27 (m, 1H), 7.95-7.88 (m, 2H), 7.76-7.67 (m, 1H), 7.60-7.54 (m, J= 8.3 Hz, 2H), 7.51- 7.44 (m, J = 8.0 Hz, 2H), 7.41 (d, J = 5.5 Hz, 2H),7.14 (d, J = 8.3 Hz, 1H), 6.66 (dd, J = 8.3, 2.5 Hz, 1H), 5.14 (s, 2H),4.25 (t, J = 8.5 Hz, 2H), 3.96 (s, 2H), 3.10 (t, J = 8.3 Hz, 2H) 273

4-(4-{2-oxo-2-[5- (propan-2-yloxy)-2,3- dihydro-1H-indol-1-yl]ethyl}phenyl)-1,2- dihydrophthalazin-1- one 440.1 A: 9.77 B: 9.24 ¹HNMR (500 MHz, DMSO-d₆) d 12.82 (s, 1H), 8.40- 8.31 (m, 1H), 7.97 (d, J =8.8 Hz, 1H), 7.94-7.86 (m, 2H), 7.78-7.69 (m, 1H), 7.60-7.52 (m, J = 8.0Hz, 2H), 7.51- 7.45 (m, J = 8.3 Hz, 2H), 6.83 (s, 1H), 6.69 (dd, J =8.8, 2.5 Hz, 1H), 4.56-4.45 (m, 1H), 4.20 (t, J = 8.4 Hz, 2H), 3.93 (s,2H), 3.20-3.07 (m, 4H), 1.29-1.19 (m, 6H) 274

4-[4-(2-oxo-2-{6- [(3R)-oxolan-3- yloxy]-2,3-dihydro-1H-indol-1-yl}ethyl) phenyl]-1,2- dihydrophthalazin-1- one 468.2 E: 1.64F: 1.64 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.38- 8.30 (m, 1H),7.93-7.85 (m, 2H), 7.79-7.69 (m, 2H), 7.63- 7.52 (m, J = 8.0 Hz, 2H),7.52-7.42 (m, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.64-6.50 (m,1H), 4.93 (br. s., 1H), 4.24 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H),3.86-3.78 (m, 2H), 3.78-3.70 (m, 2H), 3.10 (t, J = 8.3 Hz, 2H), 2.16(dd, J = 13.8, 6.1 Hz, 1H), 2.02-1.83 (m, 1H) 275

4-[4-(2-oxo-2-{6- [(3S)-oxolan-3-yloxy]- 2,3-dihydro-1H-indol-1-yl}ethyl)phenyl]- 1,2-dihydrophthalazin- 1-one 468.2 E: 1.64 F: 1.61¹H NMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.38- 8.30 (m, 1H), 7.92-7.87(m, 2H), 7.77-7.69 (m, 2H), 7.61- 7.52 (m, J = 8.0 Hz, 2H), 7.51-7.42(m, J = 8.0 Hz, 2H), 7.13 (d, J = 8.3 Hz, 1H), 6.58-6.51 (m, 1H), 4.93(br. s., 1H), 4.24 (t, J = 8.4 Hz, 2H), 3.96 (s, 2H), 3.88-3.79 (m, 2H),3.78-3.70 (m, 2H), 3.10 (t, J = 8.4 Hz, 2H), 2.22-2.12 (m, 1H),2.00-1.89 (m, 1H) 276

2-[4-(4-oxo-3,4- dihydrophthalazin-1- yl)phenyl]-N-(4,5,6,7-tetrahydro-1,2- benzoxazol-3- yl)acetamide 401.2 E: 1.44 F: 1.44 ¹H NMR(500 MHz, DMSO-d₆) d 12.86 (s, 1H), 11.08 (br. s., 1H), 8.34 (d, J = 7.2Hz, 1H), 7.94-7.87 (m, 2H), 7.70 (d, J = 7.7 Hz, 1H), 7.59-7.54 (m, J =7.7 Hz, 2H), 7.51- 7.44 (m, J = 7.7 Hz, 2H), 3.79 (s, 2H), 2.65-2.57 (m,2H), 2.44-2.32 (m, 2H), 1.69 (d, J = 5.8 Hz, 2H), 1.65-1.55 (m, 2H) 277

4-{4-[2-(6-{[(3R)-1- methylpyrrolidin-3- yl]oxy}-2,3-dihydro-1H-indol-1-yl)-2- oxoethyl]phenyl}-1,2- dihydrophthalazin-1- one 481.2E: 1.40 F: 1.40 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (br. s., 1H), 8.34 (d,J = 6.9 Hz, 1H), 7.93-7.87 (m, 2H), 7.76-7.69 (m, 2H), 7.59-7.55 (m, J =7.4 Hz, 2H), 7.49-7.41 (m, J = 7.4 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H),6.51 (d, J = 8.0 Hz, 1H), 4.75 (br. s., 1H), 4.24 (t, J = 8.3 Hz, 2H),3.96 (s, 2H), 3.09 (t, J = 8.1 Hz, 2H), 2.76-2.70 (m, 1H), 2.62 (d, J =7.4 Hz, 1H), 2.56 (d, J = 10.2 Hz, 1H), 2.40-2.29 (m, 1H), 2.27-2.16 (m,4H), 1.90 (s, 1H), 1.79-1.69 (m, 1H) 278

N-(5-tert-butyl-1,2- oxazol-3-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 403.2 E: 1.70 F: 1.74 ¹H NMR (500 MHz, DMSO-d₆) d12.85 (s, 1H), 11.29 (br. s., 1H), 8.43-8.28 (m, 1H), 7.89 (dd, J = 4.8,3.4 Hz, 2H), 7.69 (d, J = 7.4 Hz, 1H), 7.59-7.53 (m, J = 7.4 Hz, 2H),7.53- 7.43 (m, J = 7.7 Hz, 2H), 6.60 (s, 1H), 3.90 (s, 1H), 3.78 (s,2H), 1.28 (s, 9H) 279

4-[4-(2-{6-[2- (dimethylamino) ethoxy]-2,3-dihydro- 1H-indol-1-yl}-2-oxoethyl)phenyl]-1,2- dihydrophthalazin-1- one 469.1 E: 1.27 F: 1.27 ¹HNMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.34 (d, J = 6.9 Hz, 1H), 7.90(d, J = 3.6 Hz, 2H), 7.81-7.69 (m, 2H), 7.61-7.51 (m, J = 7.4 Hz, 2H),7.50-7.38 (m, J = 7.4 Hz, 2H), 7.12 (d, J = 8.3 Hz, 1H), 6.58 (d, J =8.0 Hz, 1H), 4.24 (t, J = 8.3 Hz, 2H), 4.07-3.95 (m, 4H), 3.10 (t, J =8.1 Hz, 2H), 2.62 (br. s., 2H), 2.22 (s, 6H) 280

N-(dimethyl-1,2- oxazol-3-yl)-2-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetamide 375.2 E: 1.29 F: 1.30 ¹H NMR (500 MHz, DMSO-d₆) d12.86 (br. s., 1H), 10.51 (br. s., 1H), 8.34 (d, J = 7.2 Hz, 1H),8.02-7.81 (m, 3H), 7.70 (d, J = 6.9 Hz, 1H), 7.61-7.54 (m, J = 7.4 Hz,2H), 7.53- 7.44 (m, J = 7.4 Hz, 2H), 3.80 (s, 2H), 2.30 (s, 3H), 1.78(s, 3H) 281

4-{4-[2-(6-{[(3S)-1- methylpyrrolidin-3- yl]oxy}-2,3-dihydro-1H-indol-1-yl)-2- oxoethyl]phenyl}-1,2- dihydrophthalazin-1- one 481.2E: 1.31 F: 1.34 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (s, 1H), 8.34 (d, J =6.9 Hz, 1H), 7.96-7.84 (m, 2H), 7.79-7.69 (m, 2H), 7.66-7.54 (m, J = 7.7Hz, 2H), 7.51-7.42 (m, J = 7.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.52(d, J = 8.0 Hz, 1H), 4.76 (br. s., 1H), 4.24 (t, J = 8.3 Hz, 2H), 3.96(s, 2H), 3.09 (t, J = 8.3 Hz, 2H), 2.78-2.72 (m, 1H), 2.65 (d, J = 6.9Hz, 1H), 2.59 (d, J = 10.2 Hz, 1H), 2.39-2.34 (m, 1H), 2.30-2.20 (m,4H), 1.79-1.69 (m, 1H) 282

4-[4-(2-{6-[(1- methylpiperidin-4- yl)oxy]-2,3-dihydro-1H-indol-1-yl}-2- oxoethyl)phenyl]-1,2- dihydrophthalazin-1- one 495.1E: 1.35 F: 1.35 ¹H NMR (500 MHz, DMSO-d₆) d 12.87 (s, 1H), 9.46 (br. s.,1H), 8.35 (d, J = 6.3 Hz, 1H), 7.95 (s, 1H), 7.91 (d, J = 3.6 Hz, 2H),7.83 (br. s., 1H), 7.72 (br. s., 1H), 7.63-7.53 (m, J = 7.7 Hz, 2H),7.50-7.42 (m, J = 7.4 Hz, 2H), 7.19-7.09 (m, 1H), 6.72-6.61 (m, 1H),4.25 (t, J = 8.0 Hz, 2H), 3.97 (br. s., 2H), 3.31 (d, J = 12.1 Hz, 2H),3.20-3.04 (m, 4H), 2.89 (s, 2H), 2.82 (br. s., 2H), 2.77 (br. s., 1H),2.73 (s, 2H), 2.55 (br. s., 1H), 2.20 (d, J = 13.2 Hz, 1H), 2.09-2.00(m, 1H), 1.99-1.88 (m, 1H), 1.70 (q, J = 12.1 Hz, 1H) 283

methyl 2-[(1-{2-[4-(4- oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetyl}-2,3- dihydro-1H-indol-6- yl)oxy]acetate 470.1 A: 8.46B: 8.47 ¹H NMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.39- 8.32 (m, 1H),7.95-7.86 (m, 2H), 7.77-7.70 (m, 2H), 7.61- 7.53 (m, J = 8.3 Hz, 2H),7.51-7.44 (m, J = 8.3 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 6.57 (dd, J =8.3, 2.5 Hz, 1H), 4.72 (s, 2H), 4.25 (t, J = 8.5 Hz, 2H), 3.96 (s, 2H),3.76-3.59 (m, 3H), 3.10 (t, J = 8.3 Hz, 2H) 284

4-(4-{2-[6-(oxetan-3- ylmethoxy)-2,3- dihydro-1H-indol-1-yl]-2-oxoethyl} phenyl)-1,2- dihydrophthalazin-1- one 468.2 E: 1.61 F:1.61 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (br. s., 1H), 8.34 (d, J = 6.1Hz, 1H), 7.90 (br. s., 2H), 7.78 (br. s., 1H), 7.72 (d, J = 6.6 Hz, 1H),7.56 (d, J = 6.9 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.13 (d, J = 7.2 Hz,1H), 6.60 (d, J = 7.7 Hz, 1H), 4.68 (br. s., 2H), 4.40 (br. s., 2H),4.25 (t, J = 7.6 Hz, 2H), 4.13 (d, J = 5.2 Hz, 2H), 3.97 (br. s., 2H),3.10 (t, J = 7.3 Hz, 2H), 1.23 (br. s., 1H) 285

4-{4-[2-(6-nitro-2,3- dihydro-1H-indol-1- yl)-2-oxoethyl] phenyl}-1,2-dihydrophthalazin-1- one 427.1 E: 1.70 F: 1.65 ¹H NMR (500 MHz, DMSO-d₆)d 12.86 (br. s., 1H), 8.84 (br. s., 1H), 8.39-8.30 (m, 1H), 8.02-7.87(m, 3H), 7.73 (br. s., 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.54-7.45 (m, 3H),4.36 (t, J = 8.0 Hz, 2H), 4.03 (br. s., 2H) 286

4-[4-(2-oxo-2-{6-[2- (pyrrolidin-1-yl) ethoxy]-2,3-dihydro-1H-indol-1-yl}ethyl) phenyl]-1,2- dihydrophthalazin-1- one 495.2 E: 1.27F: 1.31 ¹H NMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.41- 8.28 (m, 1H),7.94-7.84 (m, 2H), 7.78-7.68 (m, 2H), 7.63- 7.51 (m, J = 8.3 Hz, 2H),7.49-7.41 (m, J = 8.0 Hz, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.58 (dd, J =8.3, 2.5 Hz, 1H), 4.24 (t, J = 8.4 Hz, 2H), 4.07-3.92 (m, 4H), 3.10 (t,J = 8.4 Hz, 2H), 2.81-2.69 (m, 2H), 1.66 (dt, J = 6.7, 3.1 Hz, 4H) 291

N,N-dimethyl-1-{2-[4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]acetyl}-2,3- dihydro-1H-indole-6- carboxamide 453.2 E: 1.53 F:1.50 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (br. s., 1H), 8.34 (d, J = 6.3Hz, 1H), 8.09 (br. s., 1H), 7.91-7.85 (m, 2H), 7.72 (d, J = 6.6 Hz, 1H),7.62-7.53 (m, J = 7.2 Hz, 2H), 7.50- 7.41 (m, J = 7.2 Hz, 2H), 7.30 (d,J = 7.2 Hz, 1H), 7.03 (d, J = 7.4 Hz, 1H), 4.33-4.21 (m, 2H), 3.98 (br.s., 2H), 3.22 (t, J = 8.1 Hz, 2H), 2.96 (br. s., 3H), 2.89 (br. s., 3H)292

4-(4-{2-[6-(4- methylpiperazine-1- carbonyl)-2,3-dihydro-1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 508.3E: 1.33 F: 1.44 ¹H NMR (500 MHz, DMSO-d₆) d 12.86 (br. s., 1H), 8.34 (d,J = 6.3 Hz, 1H), 8.08 (br. s., 1H), 7.90 (br. s., 2H), 7.72 (d, J = 6.1Hz, 1H), 7.60-7.53 (m, J = 7.4 Hz, 2H), 7.51- 7.45 (m, J = 7.4 Hz, 2H),7.31 (d, J = 7.4 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 4.27 (t, J = 7.8 Hz,2H), 4.04-3.94 (m, 2H), 3.58 (br. s., 2H), 3.22 (t, J = 7.8 Hz, 2H),2.32 (br. s., 2H), 2.24 (br. s., 2H), 2.17 (br. s., 3H) 293

4-(4-{2-[6- (morpholine-4- carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2-oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 495.2 E: 1.35 F: 1.35 ¹HNMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.37- 8.30 (m, 1H), 8.11 (s,1H), 7.92-7.86 (m, 2H), 7.74-7.69 (m, 1H), 7.59-7.54 (m, J = 8.3 Hz,2H), 7.51-7.44 (m, J = 8.0 Hz, 2H), 7.31 (d, J = 7.4 Hz, 1H), 7.04 (dd,J = 7.7, 1.4 Hz, 1H), 4.27 (t, J = 8.5 Hz, 2H), 4.04-3.93 (m, 2H), 3.57(br. s., 6H), 3.22 (t, J = 8.4 Hz, 2H) 294

4-(4-{2-[5-(4- hydroxypiperidine-1- carbonyl)-2,3-dihydro-1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 509.2E: 1.21 F: 1.27 ¹H NMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.38- 8.31(m, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.94-7.86 (m, 2H), 7.76-7.69 (m, 1H),7.60-7.54 (m, J = 8.3 Hz, 2H), 7.50- 7.44 (m, J = 8.0 Hz, 2H), 7.27 (s,1H), 7.19 (d, J = 8.3 Hz, 1H), 4.76 (d, J = 4.1 Hz, 1H), 4.26 (t, J =8.5 Hz, 2H), 3.99 (s, 2H), 3.90 (s, 2H), 3.72 (ddt, J = 12.1, 8.1, 3.8Hz, 1H, 3.25- 3.10 (m, 4H), 1.73 (br. s., 2H), 1.34 (br. s., 2H) 295

4-(4-{2-[6-(4- hydroxypiperidine-1- carbonyl)-2,3-dihydro-1H-indol-1-yl]-2- oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 509.2E: 1.32 F: 1.32 ¹H NMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.40- 8.31(m, 1H), 8.08 (s, 1H), 7.92-7.86 (m, 2H), 7.75-7.69 (m, 1H), 7.59-7.53(m, J = 8.0 Hz, 2H), 7.53-7.45 (m, J = 8.0 Hz, 2H), 7.30 (d, J = 7.7 Hz,1H), 7.00 (dd, J = 7.4, 1.1 Hz, 1H), 4.75 (d, J = 4.1 Hz, 1H), 4.27 (t,J = 8.4 Hz, 2H), 4.05-3.91 (m, 3H), 3.71 (td, J = 8.0, 4.1 Hz, 1H), 3.51(s, 1H), 3.22 (t, J = 8.5 Hz, 2H), 3.13 (br. s., 2H), 1.75 (br. s., 1H),1.68 (br. s., 1H), 1.40 (br. s., 1H), 1.35-1.23 (m, 7H) 296

4-(4-{2-[5- (morpholine-4- carbonyl)-2,3-dihydro- 1H-indol-1-yl]-2-oxoethyl}phenyl)-1,2- dihydrophthalazin-1- one 495.2 E: 1.38 F: 1.38 ¹HNMR (500 MHz, DMSO-d₆) d 12.83 (s, 1H), 8.37- 8.29 (m, 1H), 8.10 (d, J =8.0 Hz, 1H), 7.93-7.86 (m, 2H), 7.75-7.70 (m, 1H), 7.61-7.54 (m, J = 8.0Hz, 2H), 7.50- 7.45 (m, J = 8.0 Hz, 2H), 7.31 (s, 1H), 7.23 (d, J = 8.3Hz, 1H), 4.27 (t, J = 8.4 Hz, 2H), 3.99 (s, 2H), 3.59 (br. s., 4H), 3.48(br. s., 4H), 3.21 (t, J = 8.3 Hz, 2H)

Example 287:4-(2-Fluoro-4-(2-(indolin-1-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof Intermediate 6 (15 mg, 0.067 mmol) and Intermediate 72 (33.2 mg,0.087 mmol), afforded 10.6 mg (31%) of Example 287. MS(ESI) m/z: 399.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.55 (br. s., 1H), 8.28 (dd, J=8.1,1.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.69 (ddd, J=8.3, 7.1, 1.4 Hz, 1H),7.58-7.50 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.32-7.27 (m, 1H), 7.27-7.20(m, 3H), 7.19-7.12 (m, 2H), 7.04-6.97 (m, 1H), 4.23 (t, J=8.5 Hz, 2H),3.97 (s, 2H), 3.19 (t, J=8.5 Hz, 2H); HPLC RT=1.76 min (Method E), 1.76min (Method F).

Example 288:4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)isoquinolin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof Intermediate 6 (20 mg, 0.089 mmol) and Intermediate 87 (40.3 mg,0.089 mmol), afforded 11.9 mg (28%) of Example 287. MS(ESI) m/z: 469.3(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.47 (d, J=5.5 Hz, 1H), 8.33-8.27(m, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.73-7.67 (m, 1H), 7.58-7.51 (m, 2H),7.40 (s, 4H), 7.13-7.06 (m, 2H), 6.57 (dd, J=8.1, 2.3 Hz, 1H), 4.62 (s,1H), 4.23 (t, J=8.5 Hz, 2H), 3.91 (d, J=7.2 Hz, 2H), 3.63 (s, 2H), 3.09(t, J=8.4 Hz, 2H), 1.18 (s, 6H); HPLC RT=1.70 min (Method E), 1.69 min(Method F).

Example 289:4-(4-(2-(6-(2-Hydroxy-2-methylpropoxy)indolin-1-yl)-2-oxoethyl)phenyl)-6-methoxyisoquinolin-1(2H)-one

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (22 mg, 0.087 mmol) and Intermediate 87 (39.1 mg,0.087 mmol) afforded 12.4 mg (29%) of Example 289. MS(ESI) m/z: 499.3(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.30 (d, J=5.8 Hz, 1H), 8.23 (d,J=9.1 Hz, 1H), 7.76 (d, J=1.9 Hz, 1H), 7.48-7.37 (m, 4H), 7.23-7.09 (m,2H), 7.06 (d, J=5.5 Hz, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.57 (dd, J=8.1,2.3 Hz, 1H), 4.61 (s, 1H), 4.23 (t, J=8.4 Hz, 2H), 3.92 (s, 2H), 3.77(s, 3H), 3.63 (s, 2H), 3.09 (t, J=8.4 Hz, 2H), 1.17 (s, 6H); HPLCRT=1.70 min (Method E), 1.70 min (Method F).

Example 290:2-((1-(2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetyl)indolin-6-yl)oxy)aceticacid

A mixture of Example 283 (32 mg, 0.068 mmol) and 1M lithium hydroxide(0.2 mL, 0.200 mmol) in THF (2 mL) was stirred rt for 2 h. The mixturewas concentrated, then was purified by prep HPLC to afford Example 290(28 mg, 90% yield). MS(ESI) m/z: 456.0 (M+H)⁺; ¹H NMR (500 MHz,methanol-d₄) δ 8.50-8.44 (m, 1H), 7.96-7.84 (m, 4H), 7.63-7.58 (m, 2H),7.57-7.52 (m, 2H), 7.11 (d, J=8.3 Hz, 1H), 6.64 (dd, J=8.3, 2.5 Hz, 1H),4.62 (s, 2H), 4.27 (t, J=8.4 Hz, 2H), 4.00 (s, 2H), 3.16 (t, J=8.3 Hz,2H); HPLC RT=7.44 min (Method A), 7.57 min (Method B).

Example 297:4-(4-(2-(6-(2-Morpholino-2-oxoethoxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

To a solution of Example 290 (8 mg, 0.018 mmol), morpholine (3.06 mg,0.035 mmol), and HATU (10.02 mg, 0.026 mmol) in DMF (1 mL), was add DIEA(0.015 mL, 0.088 mmol). The mixture was stirred rt for 1 h, then waspurified by prep HPLC to afford Example 297 (6.1 mg, 64% yield). MS(ESI)m/z: 525.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (br. s., 1H), 8.34(d, J=6.1 Hz, 1H), 7.90 (br. s., 2H), 7.73 (br. s., 2H), 7.56 (d, J=6.6Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.12 (d, J=5.8 Hz, 1H), 6.57 (d, J=8.0Hz, 1H), 4.75 (br. s., 2H), 4.24 (t, J=7.4 Hz, 2H), 3.96 (br. s., 2H),3.59 (br. s., 2H), 3.55 (br. s., 2H), 3.44 (d, J=11.8 Hz, 4H), 3.10 (t,J=7.6 Hz, 2H); HPLC RT=1.45 min (Method E), 1.45 min (Method F).

Example 298:2-((1-(2-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetyl)indolin-6-yl)oxy)acetamide

According to the procedure for the preparation of Example 297, couplingof Example 290 (8 mg, 0.018 mmol) and ammonium chloride (1.9 mg, 0.035mmol) afforded Example 298 (5.1 mg, 63% yield). MS(ESI) m/z: 455.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (br. s., 1H), 8.34 (d, J=6.3Hz, 1H), 7.90 (br. s., 2H), 7.79 (br. s., 1H), 7.73 (d, J=6.6 Hz, 1H),7.56 (d, J=7.4 Hz, 2H), 7.53-7.45 (m, 3H), 7.35 (br. s., 1H), 7.13 (d,J=6.3 Hz, 1H), 6.65-6.55 (m, 1H), 4.35 (br. s., 2H), 4.24 (t, J=7.8 Hz,2H), 3.96 (br. s., 2H), 3.10 (t, J=7.8 Hz, 2H); HPLC RT=1.48 min (MethodE), 1.49 min (Method F).

Example 299:4-(4-(2-(6-(2-(4-Methylpiperazin-1-yl)-2-oxoethoxy)indolin-1-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one

According to the procedure for the preparation of Example 297, couplingof Example 290 (8 mg, 0.018 mmol) and 1-methylpiperazine (4.40 mg, 0.044mmol) afforded Example 299 (1.2 mg, 9% yield). MS(ESI) m/z: 538.4(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.87 (br. s., 1H), 9.98 (br. s.,1H), 8.40-8.29 (m, 1H), 7.91 (br. s., 2H), 7.76-7.67 (m, 2H), 7.57 (d,J=6.9 Hz, 2H), 7.46 (d, J=6.9 Hz, 2H), 7.19-7.09 (m, 1H), 6.59 (d, J=7.7Hz, 1H), 4.87 (br. s., 1H), 4.79 (br. s., 1H), 4.39 (br. s., 1H), 4.26(br. s., 2H), 4.06 (br. s., 1H), 3.98 (br. s., 2H), 3.17-3.04 (m, 3H),2.65 (br. s., 3H); HPLC RT=1.30 min (Method E), 1.30 min (Method F).

Example 300:4-(Dimethylamino)-N-(1-(2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetyl)indolin-6-yl)benzamide

According to the procedure for the preparation of Example 3, coupling ofIntermediate 1 (11 mg, 0.039 mmol), and Intermediate 95 (22 mg, 0.043mmol) afforded Example 300 (8.6 mg, 40% yield). MS(ESI) m/z: 544.3(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 9.81 (s, 1H),8.38-8.31 (m, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92-7.81 (m, 4H), 7.76-7.69(m, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 3H), 6.75 (d, J=9.1Hz, 2H), 4.24 (t, J=8.5 Hz, 2H), 3.96 (s, 2H), 3.19 (t, J=8.4 Hz, 2H),2.99 (s, 6H); HPLC RT=1.55 min (Method E), 1.70 min (Method F).

The following Examples in Table 5 were made by using the same procedureas shown in Example 45. Intermediate 94 was coupled with the appropriatecarboxylic acid. Various coupling reagents could be used other than theone described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.

TABLE 5 HPLC LCMS Method, Ex- (M + RT ample R IUPAC name H)⁺ (min.) ¹HNMR 301

1-(2-hydroxy-2- methypropyl)-N-[3- methyl-4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole-3- carboxamide 468.2 E: 1.64F: 1.67 ¹H NMR (500 MHz, DMSO-d₆) d 12.79 (s, 1H), 10.27 (s, 1H),8.38-8.30 (m, 1H), 8.24 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H),7.90-7.83 (m, 4H), 7.48 (td, J = 7.7, 0.8 Hz, 1H), 7.36-7.25 (m, 3H),4.77 (s, 1H), 4.48 (s, 2H), 2.11 (s, 3H), 1.20 (s, 6H) 302

1-(2-hydroxy-2- methylpropyl)-N-[3- methyl-4-(4-oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indole-3- carboxamide 467.1 E: 7.85F: 7.05 ¹H NMR (400 MHz, methanol-d₄) d 8.48-8.41 (m, 1H), 8.23 (d, J =7.5 Hz, 1H), 8.15 (s, 1H), 7.93-7.83 (m, 2H), 7.76 (d, J = 1.8 Hz, 1H),7.71 (dd, J = 8.3, 2.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.47-7.40 (m,1H), 7.34-7.24 (m, 2H), 7.24-7.18 (m, 1H), 4.23 (s, 2H), 2.16 (s, 3H),1.25 (s, 6H) 303

1-[2-(dimethylamino) ethyl]-N-[3-methyl-4-(4- oxo-3,4-dihydrophthalazin-1- yl)phenyl]-1H-indazole-3- carboxamide 467.3 E: 1.33F: 1.53 ¹H NMR (500 MHz, DMSO-d₆) d 12.80 (s, 1H), 10.29 (s, 1H), 9.39(br. s., 1H), 8.38-8.33 (m, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.95-7.80 (m,5H), 7.59 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.35 (d, J =8.3 Hz, 1H), 7.32-7.25 (m, 1H), 4.96 (t, J = 5.9 Hz, 2H), 3.80 (br. s.,2H), 2.95 (br. s., 6H), 2.12 (s, 3H) 304

2-[2-(dimethylamino) ethyl]-N-[3-methyl-4-(4- oxo-3,4-dihydrophthalazin-1- yl)phenyl]-2H-indazole-3- carboxamide 467.2 A: 1.31B: 1.45 ¹H NMR (500 MHz, DMSO-d₆) d 12.80 (s, 1H), 10.93 (s, 1H),8.41-8.31 (m, 1H), 7.91-7.81 (m, 4H), 7.80- 7.71 (m, 2H), 7.45-7.35 (m,2H), 7.32-7.24 (m, 2H), 4.84 (t, J = 6.2 Hz, 2H), 2.83 (t, J = 6.3 Hz,2H), 2.17 (s, 6H), 2.11 (s, 3H) 305

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-2-(oxetan-3-ylmethyl)-2H-indazole-3- carboxamide 466.2 E: 1.09 F: 1.08 ¹H NMR (500MHz, DMSO-d₆) d 12.84 (s, 1H), 11.28 (s, 1H), 8.38-8.33 (m, 1H), 8.31(d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 8.00-7.93 (m, 1H),7.92-7.86 (m, 2H), 7.84 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.70 (t, J =7.7 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 5.16(dd, J = 13.3, 8.1 Hz, 2H), 5.01-4.87 (m, 2H), 4.70 (dd, J = 11.3, 4.7Hz, 1H), 3.73 (br. s., 2H), 3.67-3.59 (m, 1H), 2.14 (s, 3H) 306

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-2,1-benzoxazole-3- carboxamide 397.1 E: 1.68 F: 1.68 ¹H NMR (500 MHz,DMSO-d₆) d 12.81 (s, 1H), 11.23 (s, 1H), 8.40-8.28 (m, 1H), 8.05 (d, J =8.8 Hz, 1H), 7.96 (s, 1H), 7.90-7.81 (m, 4H), 7.55 (dd, J = 9.2, 6.5 Hz,1H), 7.40-7.32 (m, 2H), 7.31-7.25 (m, 1H), 2.11 (s, 3H) 307

benzyl 4-[(3-{[3-methyl- 4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H- indazol-1-yl)methyl] piperidine-1-carboxylate672.2 A: 11.59 B: 9.87 ¹H NMR (400 MHz, DMSO-d₆) d 12.79 (s, 1H), 10.34(s, 1H), 8.37-8.31 (m, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.92-7.82 (m, 4H), 7.51 (ddd, J = 8.4, 7.0, 1.1 Hz, 1H),7.41-7.23 (m, 7H), 5.06 (s, 2H), 4.48 (d, J = 7.0 Hz, 2H), 4.02 (d, J =13.0 Hz, 2H), 2.78 (br. s., 2H), 2.36-2.19 (m, 1H), 2.16-2.03 (m, 3H),1.51 (d, J = 11.0 Hz, 2H), 1.26 (qd, J = 12.4, 4.1 Hz, 2H) 308

5-fluoro-N-[3-methyl-4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-pyrrolo[2,3-b] pyridine-3-carboxamide 414.2 E: 1.44 F: 1.44¹H NMR (500 MHz, DMSO-d₆) d 12.78 (s, 1H), 12.48 (br. s., 1H), 9.98 (s,1H), 8.58 (d, J = 2.5 Hz, 1H), 8.33 (br. s., 2H), 8.26 (dd, J = 9.4, 2.8Hz, 1H), 7.95 (s, 1H), 7.90-7.84 (m, 2H), 7.81 (s, 1H), 7.76 (d, J = 8.3Hz, 1H), 7.30-7.25 (m, 1H), 2.10 (s, 3H) 309

7-methoxy-N-[3-methyl- 4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]-1H-indole-2- carboxamide 425.2 E: 1.72 F: 1.73 ¹H NMR (500MHz, DMSO-d₆) d 12.79 (s, 1H), 11.62 (s, 1H), 10.26 (s, 1H), 8.40-8.21(m, 1H), 7.90-7.84 (m, 2H), 7.84-7.76 (m, 2H), 7.38-7.23 (m, 4H), 7.03(t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 3.97 (s, 3H), 3.90 (s,1H), 2.11 (s, 3H) 310

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide 396.2 E: 1.45 F: 1.45 ¹H NMR (500 MHz, DMSO-d₆) d12.78 (s, 1H), 10.06 (s, 1H), 8.90-8.81 (m, 2H), 8.38-8.27 (m, 2H),7.91- 7.85 (m, 2H), 7.82 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.60- 7.52(m, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 6.9 Hz, 1H), 3.90 (s,1H), 2.10 (s, 3H) 311

2-methyl-N-[3-methyl-4- (4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]imidazo[1,2-a] pyridine-3-carboxamide 410.2 E: 1.08 F: 1.40 ¹HNMR (500 MHz, DMSO-d₆) d 12.79 (s, 1H), 10.02 (s, 1H), 8.96 (d, J = 6.9Hz, 1H), 8.33 (d, J = 4.7 Hz, 1H), 7.91-7.84 (m, 2H), 7.76 (s, 1H), 7.71(d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H),7.36-7.26 (m, 2H), 7.11-7.06 (m, 1H), 2.68 (s, 3H), 2.10 (s, 3H) 312

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide 396.2 E: 1.09 F: 1.14 ¹H NMR (500 MHz, DMSO-d₆) d12.79 (s, 1H), 10.31 (s, 1H), 9.51 (d, J = 7.2 Hz, 1H), 8.64 (s, 1H),8.39-8.29 (m, 1H), 7.87 (dd, J = 4.8, 2.6 Hz, 2H), 7.83-7.73 (m, 3H),7.54 (t, J = 7.8 Hz, 1H), 7.37-7.26 (m, 2H), 7.20 (t, J = 6.7 Hz, 1H),2.11 (s, 3H) 313

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-(oxan-4-ylmethyl)-1H-indazole-3- carboxamide 494.2 E: 1.86 F: 1.90 ¹H NMR (500MHz, DMSO-d₆) d 12.79 (s, 1H), 10.34 (s, 1H), 8.37-8.30 (m, 1H), 8.25(d, J = 8.0 Hz, 1H), 7.97 (s, 1H), 7.93-7.85 (m, 4H), 7.51 (t, J = 7.4Hz, 1H), 7.40-7.26 (m, 3H), 4.48 (d, J = 6.9 Hz, 2H), 3.84 (d, J = 10.7Hz, 2H), 3.29-3.18 (m, 2H), 2.37-2.24 (m, 1H), 2.10 (s, 3H), 1.40 (br.s., 4H) 314

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-[(3-methyloxetan-3- yl)methyl]-1H-indazole- 3-carboxamide 480.3 A: 1.68 B:1.67 ¹H NMR (500 MHz, DMSO-d₆) d 12.79 (br. s., 1H), 10.23 (br. s., 1H),8.34 (d, J = 4.4 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.93 (br. s., 1H),7.91-7.82 (m, 4H), 7.53 (t, J = 7.2 Hz, 1H), 7.41-7.27 (m, 3H), 4.80(br. s., 4H), 4.33 (d, J = 5.0 Hz, 2H), 3.90 (s, 1H), 2.11 (br. s., 3H),1.20 (br. s., 3H) 325

N-[3-methyl-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-6-[2-(pyrrolidin-1-yl)ethoxy] pyrazolo[1,5-a]pyridine- 3-carboxamide 509.2 E:1.18 F: 1.14 ¹H NMR (500 MHz, DMSO-d₆) d 12.79 (s, 1H), 10.06 (s, 1H),8.76 (s, 1H), 8.65 (s, 1H), 8.40-8.30 (m, 1H), 8.23 (d, J = 9.8 Hz, 1H),7.91-7.85 (m, 2H), 7.83-7.73 (m, 2H), 7.41 (d, J = 9.5 Hz, 1H),7.32-7.22 (m, 2H), 4.35 (br. s., 2H), 2.09 (s, 3H), 1.90 (br. s., 4H)

The following Examples in Table 6 were made by using the same procedureas shown in Example 45. Intermediate 96 was coupled with the appropriatecarboxylic acid. Various coupling reagents could be used other than theone described in Example 45, such as BOP, PyBop, EDC/HOBt or T3P.

TABLE 6 HPLC LCMS Method, Ex- (M + RT ample R IUPAC name H)⁺ (min.) ¹HNMR 315

N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-(2-hydroxy-2-methylpropyl)-1H- indazole-3-carboxamide 488.2 E: 1.78 F: 1.78 ¹H NMR(500 MHz, DMSO-d₆) d 12.89 (br. s., 1H), 10.62 (s, 1H), 8.40-8.30 (m,2H), 8.24 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.92-7.85 (m,3H), 7.55 (d, J = 8.3 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.37-7.28 (m,2H), 4.77 (br. s., 1H), 4.49 (s, 2H), 1.20 (s, 6H) 316

tert-butyl 3-[(3-{[3- chloro-4-(4-oxo-3,4- dihydrophthalazin-1-yl)phenyl]carbamoyl}- 1H-indazol-1-yl)methyl] azetidine-1-carboxylate585.2 A: 11.7 B: 9.80 ¹H NMR (400 MHz, methanol-d₄) d 8.48-8.41 (m, 1H),8.37-8.29 (m, 1H), 8.25 (t, J = 2.0 Hz, 1H), 7.97- 7.84 (m, 3H), 7.76(d, J = 8.6 Hz, 1H), 7.62-7.49 (m, 2H), 7.47-7.41 (m, 1H), 7.41-7.32 (m,1H), 4.79 (d, J = 7.0 Hz, 2H), 4.07 (t, J = 8.5 Hz, 2H), 3.91 (dd, J =8.8, 5.3 Hz, 2H), 1.41 (s, 9H) 317

N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]imidazo[1,2-a]pyridine-3-carboxamide 416.1 E: 1.15 F: 1.46 ¹H NMR (500 MHz, DMSO-d₆) d12.89 (s, 1H), 10.55 (s, 1H), 9.51 (d, J = 6.9 Hz, 1H), 8.68 (s, 1H),8.41- 8.26 (m, 1H), 8.18 (s, 1H), 7.93-7.86 (m, 3H), 7.83 (d, J = 9.1Hz, 1H), 7.65-7.54 (m, 2H), 7.36-7.29 (m, 1H), 7.26 (t, J = 6.9 Hz, 1H)318

N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-(oxan-4-ylmethyl)-1H-indazole-3- carboxamide 514.2 E: 1.94 B: 1.95 ¹H NMR (500MHz, DMSO-d₆) d 12.89 (s, 1H), 10.68 (s, 1H), 8.33 (br. s., 2H), 8.26(d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.92-7.85 (m, 3H),7.59-7.49 (m, 2H), 7.40-7.28 (m, 2H), 4.49 (d, J = 6.9 Hz, 2H), 3.90 (s,1H), 3.84 (d, J = 11.0 Hz, 2H), 3.29-3.20 (m, 2H), 2.34-2.23 (m, 1H),1.40 (br. s., 4H) 319

N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-(oxolan-3-ylmethyl)-1H-indazole-3- carboxamide 500.2 E: 1.77 F: 1.77 ¹H NMR (500MHz, DMSO-d₆) d 12.89 (s, 1H), 10.66 (s, 1H), 8.39-8.30 (m, 2H), 8.26(d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.94-7.85 (m, 3H),7.62-7.51 (m, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.33-7.28 (m, 1H), 4.58 (d,J = 7.2 Hz, 2H), 3.92-3.81 (m, 1H), 3.69 (q, J = 8.1 Hz, 2H), 3.64-3.57(m, 1H), 3.03-2.92 (m, 1H), 1.95 (dd, J = 12.5, 7.0 Hz, 1H), 1.72 (dd, J= 12.4, 6.3 Hz, 1H) 320

N-[3-chloro-4-(4-oxo- 3,4-dihydrophthalazin-1- yl)phenyl]-1-[(3-methyloxetan-3- yl)methyl]-1H-indazole- 3-carboxamide 500.2 E: 1.77 F:1.76 ¹H NMR (500 MHz, DMSO-d₆) d 12.89 (br. s., 1H), 10.55 (br. s., 1H),8.38-8.31 (m, 1H), 8.30 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.04 (d, J =8.3 Hz, 1H), 7.94- 7.86 (m, 3H), 7.60-7.50 (m, 2H), 7.36 (t, J = 7.6 Hz,1H), 7.33-7.28 (m, 1H), 4.86-4.77 (m, 4H), 4.37- 4.28 (m, 2H), 1.20 (s,3H)

Example 321:1-((1-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

To a degassed solution of Example 307 (24 mg, 0.038 mmol) in THF (2 mL),was added 10% Pd/C (5 mg). The mixture was stirred under H2 (balloon).The mixture was filtered, then was purified by prep HPLC to affordExample 321 (20 mg, 0.034 mmol, 88% yield). MS(ESI) m/z: 565.3 (M+H)⁺;¹H NMR (400 MHz, methanol-d₄) δ 8.48-8.43 (m, 1H), 8.33 (d, J=8.1 Hz,1H), 7.91-7.86 (m, 2H), 7.85-7.82 (m, 1H), 7.80 (dd, J=8.3, 1.9 Hz, 1H),7.73 (d, J=8.6 Hz, 1H), 7.58-7.51 (m, 1H), 7.45-7.40 (m, 1H), 7.39-7.32(m, 2H), 4.60-4.52 (m, 2H), 3.66-3.56 (m, 2H), 3.41 (d, J=13.0 Hz, 1H),3.18-3.07 (m, 1H), 3.05-2.89 (m, 2H), 2.48 (ddt, J=11.2, 7.5, 3.9 Hz,1H), 2.22-2.14 (m, 3H), 2.03-1.75 (m, 4H), 1.74-1.51 (m, 4H); HPLCRT=5.67 min (Method A), 6.19 min (Method B).

Example 322:1-((1-(4-Hydroxybutyl)piperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

Intermediate 3 (23.7 mg, 0.051 mmol) was coupled with Intermediate 21(20 mg, 0.051 mmol) according to the procedure for Example 45 to affordafter prep HPLC the amide product (21 mg, 67% yield). MS(ESI) m/z: 613.2(M+H)⁺. The residue (21 mg) was dissolved in THF (2 mL). To this mixturewas added 10% Pd/C (5 mg). The mixture was stirred under H2 (balloon)for 16 h. The mixture was filtered and purified by prep HPLC to affordExample 322 (15 mg, 79% yield). MS(ESI) m/z: 551.2 (M+H)⁺; ¹H NMR (400MHz, methanol-d₄) δ 8.46-8.42 (m, 1H), 8.32 (d, J=8.1 Hz, 1H), 8.01-7.95(m, 2H), 7.92-7.83 (m, 3H), 7.74-7.69 (m, 1H), 7.66-7.61 (m, 2H), 7.52(td, J=7.7, 0.9 Hz, 1H), 7.37-7.31 (m, 1H), 4.54 (dd, J=6.7, 3.2 Hz,2H), 3.63-3.55 (m, 2H), 3.41 (d, J=13.0 Hz, 1H), 3.18-3.05 (m, 2H),3.05-2.87 (m, 2H), 2.55-2.37 (m, 1H), 1.93 (d, J=14.7 Hz, 2H), 1.89-1.76(m, 2H), 1.75-1.53 (m, 3H); HPLC RT=5.53 min (Method A), 6.33 min(Method B).

Example 323:N-(4-(6-Methoxy-1-oxo-1,2-dihydroisoquinolin-4-yl)-3-methylphenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof Intermediate 73 (10 mg, 0.039 mmol) and Intermediate 97 (14.9 mg,0.039 mmol), afforded 2.7 mg (15%) of Example 323. MS(ESI) m/z: 426.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 11.19 (d, J=5.8 Hz, 1H), 8.55 (s,1H), 8.21 (d, J=8.8 Hz, 1H), 7.89 (d, J=8.3 Hz, 1H), 7.57 (s, 1H), 7.51(d, J=8.0 Hz, 2H), 7.21 (d, J=7.2 Hz, 1H), 7.12 (t, J=7.0 Hz, 3H), 6.96(d, J=5.8 Hz, 1H), 6.91-6.85 (m, 1H), 6.39 (s, 1H), 4.15 (t, J=8.7 Hz,2H), 3.70 (s, 3H), 3.19 (t, J=8.5 Hz, 2H), 2.06 (s, 3H); HPLC RT=1.77min (Method E), 1.78 min (Method F).

Example 324:N-(3-Methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol) and Intermediate 97(46 mg, 0.12 mmol), afforded 4.4 mg (10%) of Example 324. MS(ESI) m/z:397.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.76 (s, 1H), 8.63 (s, 1H),8.37-8.28 (m, 1H), 7.93-7.83 (m, 3H), 7.61 (s, 1H), 7.57 (d, J=8.3 Hz,1H), 7.33-7.27 (m, 1H), 7.21 (d, J=7.4 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H),7.14 (t, J=7.7 Hz, 1H), 6.92 (t, J=7.3 Hz, 1H), 4.17 (t, J=8.4 Hz, 2H),3.20 (t, J=8.5 Hz, 2H), 2.07 (s, 3H); HPLC RT=1.73 min (Method E), 1.73min (Method F).

Example 326:1-(Azetidin-3-ylmethyl)-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide,TFA

Example 326A: tert-Butyl3-((3-((3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate

To a solution of Intermediate 94 (55 mg, 0.12 mmol), Intermediate 33 (38mg, 0.12 mmol), and HATU (45.8 mg, 0.12 mmol) in DMF (1 mL), was addedDIEA (0.1 mL, 0.57 mmol). The mixture was stirred at rt for 4 h, thenwas concentrated. The residue was purified via preparative HPLC toafford Example 326A (45 mg, 70% yield). MS(ESI) m/z: 565.3 (M+H)⁺.

Example 326

Example 326A (30 mg, 0.053 mmol) was stirred with TFA (0.5 ml) in DCM (1ml) for 10 min, then was concentrated. The residue was purified by prepHPLC to afford Example 326 (30 mg, 97% yield). MS(ESI) m/z: 465.0(M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.53-8.42 (m, 1H), 8.35 (dt,J=8.2, 1.0 Hz, 1H), 7.94-7.86 (m, 2H), 7.85-7.82 (m, 1H), 7.80 (dd,J=8.4, 1.8 Hz, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.56 (ddd, J=8.4, 7.0, 1.1Hz, 1H), 7.45-7.39 (m, 1H), 7.39-7.33 (m, 2H), 4.82-4.79 (m, 2H),4.27-4.12 (m, 4H), 3.76-3.61 (m, 1H), 2.19 (s, 3H); HPLC RT=5.38 min(Method A), 5.98 min (Method B).

Example 327:1-(Azetidin-3-ylmethyl)-N-[3-chloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]-1H-indazole-3-carboxamide,TFA

Example 316 (24 mg, 0.041 mmol) stirred with TFA (0.5 ml) and DCM (2 ml)for 10 min, then was concentrated. The residue was purified viapreparative HPLC to afford Example 327 (20 mg, 81% yield). MS(ESI) m/z:485.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ 8.49-8.40 (m, 1H),8.39-8.31 (m, 1H), 8.24-8.17 (m, 1H), 7.96-7.85 (m, 3H), 7.74 (d, J=8.6Hz, 1H), 7.61-7.48 (m, 2H), 7.46-7.35 (m, 2H), 4.83-4.81 (m, 2H),4.31-4.10 (m, 4H), 3.67 (t, J=7.8 Hz, 1H); HPLC RT=5.83 min (Method A),6.83 min (Method B).

Example 328:2-(3-{[4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol-1-yl)aceticacid

To 4-chlorophthalazin-1(2H)-one (40.8 mg, 0.226 mmol), Intermediate 98(82 mg, 0.188 mmol) and phosphoric acid, potassium salt (100 mg, 0.47mmol), were added dioxane (5 mL) and water (0.56 mL). The mixture wasdegassed (evacuated and flushed with Ar (5×)). Pd(PPh₃)₄ (10.9 mg, 9.42μmol) was added, then the mixture was degassed (2×). The reaction vialwas sealed and heated in a microwave reactor at 150° C. for 25 min. Theproduct was purified by prep HPLC to afford Example 328 (20 mg, 24%yield). MS(ESI) m/z: 440.1 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.82 (s,1H), 10.60 (s, 1H), 8.40-8.32 (m, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.15-8.06(m, J=8.6 Hz, 2H), 7.97-7.87 (m, 2H), 7.82 (d, J=8.6 Hz, 1H), 7.79-7.74(m, 1H), 7.63-7.56 (m, J=8.6 Hz, 2H), 7.53 (td, J=7.7, 1.1 Hz, 1H), 7.36(t, J=7.6 Hz, 1H), 5.46 (s, 2H); HPLC RT=7.28 min (Method A), 6.64 min(Method B).

Example 329:1-((1-Acetylazetidin-3-yl)methyl)-N-(3-chloro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

Example 327 (10 mg, 0.021 mmol) was mixed with acetic anhydride (3.2 mg,0.031 mmol) and TEA (4.17 mg, 0.041 mmol) in CH₂Cl₂ (1 mL) and stirredat rt o/n. The reaction mixture was concentrated, then was purified byprep HPLC to afford Example 329 (9.6 mg, 87% yield). MS(ESI) m/z: 527.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.89 (s, 1H), 10.62 (br. s., 1H),8.38-8.31 (m, 2H), 8.26 (d, J=8.3 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H),7.98-7.92 (m, 1H), 7.92-7.85 (m, 2H), 7.60-7.50 (m, 2H), 7.37 (t, J=7.2Hz, 1H), 7.35-7.28 (m, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 7.00 (s, 1H),4.83 (br. s., 2H), 4.21 (t, J=8.3 Hz, 1H), 4.05 (br. s., 1H), 3.96-3.86(m, 1H), 3.79 (br. s., 1H), 3.25 (br. s., 2H), 2.55 (br. s., 2H), 1.74(s, 3H); HPLC RT=1.55 min (Method E), 1.55 min (Method F).

Example 330:N-(3-Methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((1-methylazetidin-3-yl)methyl)-1H-indazole-3-carboxamide

To a solution of Example 326 (10 mg, 0.017 mmol) in CH₂Cl₂ (1 mL), wereadded TEA (1.7 mg, 0.017 mmol), followed by formaldehyde (2.8 mg, 0.035mmol), acetic acid (5.2 mg, 0.086 mmol), and Na(OAc)₃BH (7.3 mg, 0.035mmol). The mixture was stirred rt for 16 h, then was concentrated andpurified by prep HPLC to afford Example 330 (3.8 mg, 46% yield). MS(ESI)m/z: 479.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (s, 1H), 10.30 (s,1H), 8.34 (d, J=4.7 Hz, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.92-7.77 (m, 4H),7.52 (t, J=7.4 Hz, 1H), 7.39-7.21 (m, 3H), 4.76 (d, J=6.9 Hz, 2H), 3.14(br. s., 4H), 3.05-2.96 (m, 1H), 2.25 (br. s., 3H), 2.10 (s, 3H); HPLCRT=1.35 min (Method E), 1.35 min (Method F).

Example 331:3-(3-((4-(4-Pxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-yl)propanoicacid Example 332: Methyl3-(3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-yl)propanoate

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (40.7 mg, 0.225 mmol) and Intermediate99 (92 mg, 0.205 mmol), afforded Example 331 (8 mg, 8.5% yield) andExample 332 (42 mg, 43% yield).

Example 331

MS(ESI) m/z: 454.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),12.45 (br. s., 1H), 10.45 (s, 1H), 8.41-8.31 (m, 1H), 8.24 (d, J=8.3 Hz,1H), 8.13-8.05 (m, 2H), 8.00-7.83 (m, 3H), 7.82-7.73 (m, 1H), 7.65-7.57(m, 2H), 7.52 (ddd, J=8.4, 7.0, 1.1 Hz, 1H), 7.39-7.29 (m, 1H), 4.77 (t,J=6.7 Hz, 2H), 3.04 (t, J=6.9 Hz, 2H)); HPLC RT=7.51 min (Method A),6.78 min (Method B).

Example 332

MS(ESI) m/z: 468.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),10.45 (s, 1H), 8.42-8.28 (m, 1H), 8.26-8.20 (m, 1H), 8.12-8.03 (m, 2H),7.97-7.83 (m, 3H), 7.83-7.73 (m, 1H), 7.67-7.59 (m, 2H), 7.53 (ddd,J=8.5, 7.1, 1.0 Hz, 1H), 7.41-7.28 (m, 1H), 4.81 (t, J=6.7 Hz, 2H), 3.58(s, 3H), 3.13 (t, J=6.7 Hz, 2H); HPLC RT=8.90 min (Method A), 7.84 min(Method B).

Example 333:1-(3-Hydroxy-3-methylbutyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 76, couplingof 4-chlorophthalazin-1(2H)-one (22.6 mg, 0.113 mmol) and Intermediate100 (51 mg, 0.125 mmol), afforded Example 333 (5.2 mg, 9.7% yield).MS(ESI) m/z: 468.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H),10.48 (s, 1H), 8.35 (dd, J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H),8.09 (d, J=8.5 Hz, 2H), 7.97-7.90 (m, 2H), 7.81-7.74 (m, 2H), 7.60 (s,1H), 7.57-7.48 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.69-4.63 (m, 2H), 4.57(br. s., 1H), 2.55 (t, J=5.0 Hz, 1H), 2.09-2.00 (m, 2H), 1.21 (s, 6H);HPLC RT=1.68 min (Method E), 1.68 min (Method F).

Example 334:1-(2-((2-Hydroxy-2-methylpropyl)amino)-2-oxoethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

To Example 328 (8 mg, 0.018 mmol), 1-amino-2-methylpropan-2-ol (3.3 mg,0.036 mmol), and HATU (7.6 mg, 0.020 mmol) in DMF (1 mL), was added DIEA(0.016 mL, 0.091 mmol). The mixture was stirred at rt for 16 h, then waspurified by prep HPLC to afford Example 334 (6 mg, 64% yield). MS(ESI)m/z: 511.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.55 (s,1H), 8.39-8.34 (m, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.18 (t, J=6.1 Hz, 1H),8.12-8.03 (m, 2H), 7.98-7.86 (m, 2H), 7.83-7.76 (m, 1H), 7.73 (d, J=8.5Hz, 1H), 7.63-7.56 (m, 2H), 7.51 (ddd, J=8.4, 7.0, 1.1 Hz, 1H),7.42-7.32 (m, 1H), 5.36 (s, 2H), 3.10 (d, J=6.1 Hz, 2H), 1.10 (s, 6H);HPLC RT=1.42 min (Method E), 1.41 min (Method F).

Example 335:1-(2-(((1-Hydroxycyclobutyl)methyl)amino)-2-oxoethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 334, couplingof Example 328 (8 mg, 0.018 mmol) and 1-(aminomethyl)cyclobutanol (3.7mg, 0.036 mmol) afforded Example 335 (2.7 mg, 26% yield). MS(ESI) m/z:523.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.81 (s, 1H), 10.57 (s, 1H),8.41-8.32 (m, 1H), 8.29-8.21 (m, 2H), 8.14-8.06 (m, 2H), 7.98-7.86 (m,3H), 7.78 (dd, J=7.8, 1.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.63-7.55 (m, 2H),7.53-7.47 (m, 1H), 7.40-7.31 (m, 1H), 5.36 (s, 2H), 3.90 (s, 1H), 3.26(d, J=5.8 Hz, 2H), 2.00-1.86 (m, 4H), 1.70-1.55 (m, 1H), 1.42 (dt,J=11.2, 9.0 Hz, 1H); HPLC RT=1.47 min (Method E), 1.46 min (Method F).

Example 336:1-(3-((2-Hydroxy-2-methylpropyl)amino)-3-oxopropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 334, couplingof Example 331 (9 mg, 0.02 mmol) and 1-amino-2-methylpropan-2-ol (3.5mg, 0.040 mmol) afforded Example 336 (7.4 mg, 65% yield). MS(ESI) m/z:525.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.44 (s, 1H),8.35 (dd, J=7.8, 1.2 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 8.12-8.05 (m,J=8.5 Hz, 2H), 7.98-7.84 (m, 3H), 7.82 (d, J=8.5 Hz, 1H), 7.78 (dd,J=7.8, 1.0 Hz, 1H), 7.63-7.58 (m, J=8.5 Hz, 2H), 7.53-7.47 (m, 1H), 7.33(t, J=7.4 Hz, 1H), 4.79 (t, J=6.7 Hz, 2H), 2.98 (d, J=6.1 Hz, 2H),2.93-2.86 (m, 2H), 0.92 (s, 6H); HPLC RT=1.46 min (Method E), 1.46 min(Method F).

Example 337:1-(3-Morpholino-3-oxopropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 334, couplingof Example 331 (9 mg, 0.02 mmol) and morpholine (3.5 mg, 0.040 mmol)afforded Example 337 (7.3 mg, 70% yield). MS(ESI) m/z: 523.2 (M+H)⁺; ¹HNMR 12.82 (s, 1H), 10.46 (s, 1H), 8.40-8.30 (m, 1H), 8.24 (d, J=8.3 Hz,1H), 8.13-8.05 (m, 2H), 7.98-7.83 (m, 3H), 7.81-7.73 (m, 1H), 7.62-7.58(m, 2H), 7.51 (ddd, J=8.3, 7.1, 0.8 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),4.80 (t, J=7.0 Hz, 2H), 3.52-3.37 (m, 8H), 3.09 (t, J=6.9 Hz, 2H); HPLCRT=1.55 min (Method E), 1.51 min (Method F).

Example 338:1-(Azetidin-3-ylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 326, couplingof Intermediate 3 and Intermediate 33, followed by TFA deprotectionafforded Example 338. MS(ESI) m/z: 451.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.83 (s, 1H), 10.40 (s, 1H), 8.68 (br. s., 1H), 8.52 (br.s., 1H), 8.40-8.34 (m, 1H), 8.29-8.23 (m, 1H), 8.09-8.03 (m, 2H),7.97-7.85 (m, 3H), 7.80-7.72 (m, 1H), 7.67-7.60 (m, 2H), 7.57 (ddd,J=8.4, 7.0, 1.1 Hz, 1H), 7.41-7.35 (m, 1H), 4.81 (d, J=6.9 Hz, 2H),4.14-4.02 (m, 2H), 3.99-3.87 (m, 2H); HPLC RT=5.09 min (Method A), 5.73min (Method B).

Example 339:1-((1-Acetylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 329, acylationof Example 338 (9 mg, 0.016 mmol) with acetic anhydride afforded Example339 (5.0 mg, 63% yield). MS(ESI) m/z: 493.3 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ 12.85 (s, 1H), 10.46 (s, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.25(d, J=8.0 Hz, 1H), 8.11-8.06 (m, J=8.3 Hz, 2H), 7.97-7.90 (m, 3H), 7.78(d, J=7.7 Hz, 1H), 7.64-7.58 (m, J=8.5 Hz, 2H), 7.54 (t, J=7.7 Hz, 1H),7.36 (t, J=7.4 Hz, 1H), 4.83 (dd, J=6.9, 4.7 Hz, 2H), 4.21 (t, J=8.4 Hz,1H), 4.05 (dd, J=8.1, 5.6 Hz, 1H), 3.97-3.89 (m, 2H), 3.79 (dd, J=9.4,5.5 Hz, 1H), 3.30-3.19 (m, 1H), 1.74 (s, 3H); HPLC RT=1.48 min (MethodE), 1.47 min (Method F).

Example 340:1-((1-Methylazetidin-3-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 330, reductiveamination of Example 339 (12 mg, 0.021 mmol) afforded Example 340 (9.1mg, 90% yield). MS(ESI) m/z: 465.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.86 (s, 1H), 10.41 (d, J=13.5 Hz, 1H), 9.82 (br. s., 1H), 8.36 (d,J=7.7 Hz, 1H), 8.30-8.24 (m, 1H), 8.11-8.03 (m, J=8.3 Hz, 2H), 7.98-7.87(m, 3H), 7.77 (d, J=7.7 Hz, 1H), 7.65-7.60 (m, J=8.3 Hz, 2H), 7.57 (t,J=7.6 Hz, 1H), 7.38 (t, J=7.4 Hz, 1H), 4.84 (t, J=7.3 Hz, 2H), 4.31 (d,J=5.5 Hz, 1H), 4.27-4.14 (m, 1H), 4.03 (d, J=6.9 Hz, 2H), 2.85 (dd,J=16.4, 4.5 Hz, 3H); HPLC RT=1.33 min (Method E), 1.36 min (Method F).

Example 341: Methyl3-((3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-yl)methyl)azetidine-1-carboxylate

According to the procedure for the preparation of Example 329, acylationof Example 338 (8 mg, 0.014 mmol) with methyl chloroformate affordedExample 341 (5.1 mg, 67% yield). MS(ESI) m/z: 509.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.46 (s, 1H), 8.35 (d, J=7.7 Hz, 1H),8.25 (d, J=8.0 Hz, 1H), 8.12-8.04 (m, J=8.0 Hz, 2H), 7.97-7.88 (m, 3H),7.78 (d, J=7.7 Hz, 1H), 7.63-7.59 (m, J=8.0 Hz, 2H), 7.53 (t, J=7.7 Hz,1H), 7.35 (t, J=7.6 Hz, 1H), 4.82 (d, J=7.2 Hz, 2H), 4.01 (br. s., 2H),3.93-3.84 (m, 2H), 3.54 (s, 3H), 3.27-3.14 (m, 1H); HPLC RT=1.74 min(Method E), 1.74 min (Method F).

Example 342:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(piperidin-4-ylmethyl)-1H-indazole-3-carboxamide,TFA

According to the procedure for the preparation of Example 45, couplingof Intermediate 3 (95 mg, 0.20 mmol) and Intermediate 101 (88 mg, 0.245mmol), afforded after TFA deprotection Example 342 (78 mg, 79% yield).MS(ESI) m/z: 479.4 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H),10.49 (s, 1H), 8.48 (d, J=9.9 Hz, 1H), 8.38-8.34 (m, 1H), 8.27 (d, J=8.0Hz, 1H), 8.15 (d, J=11.3 Hz, 1H), 8.11-8.07 (m, 2H), 7.94-7.88 (m, 3H),7.79-7.74 (m, 1H), 7.64-7.59 (m, 2H), 7.54 (ddd, J=8.4, 7.0, 1.1 Hz,1H), 7.39-7.33 (m, 1H), 4.55 (d, J=6.6 Hz, 2H), 3.27 (d, J=12.4 Hz, 2H),2.93-2.80 (m, 2H), 2.39-2.27 (m, 1H), 1.71 (d, J=13.8 Hz, 2H), 1.54-1.39(m, 2H); HPLC RT=8.74 min (Method A), 9.34 min (Method B).

Example 343:1-((1-Acetylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 329, acylationof Example 342 (12 mg, 0.020 mmol) with acetic anhydride affordedExample 343 (8.9 mg, 84% yield). MS(ESI) m/z: 521.3 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.52 (s, 1H), 8.35 (d, J=7.4 Hz, 1H),8.25 (d, J=8.0 Hz, 1H), 8.14-8.04 (m, J=8.0 Hz, 2H), 7.98-7.87 (m, 3H),7.78 (d, J=7.4 Hz, 1H), 7.62-7.58 (m, J=7.7 Hz, 2H), 7.52 (t, J=7.6 Hz,1H), 7.34 (t, J=7.2 Hz, 1H), 4.49 (d, J=6.6 Hz, 2H), 4.37 (d, J=12.4 Hz,1H), 3.80 (d, J=13.5 Hz, 1H), 2.96 (t, J=12.9 Hz, 1H), 2.30 (br. s.,1H), 1.97 (s, 3H), 1.50 (t, J=15.5 Hz, 2H), 1.37-1.25 (m, 1H), 1.18 (d,J=12.1 Hz, 1H); HPLC RT=1.61 min (Method E), 1.61 min (Method F).

Example 344: Methyl4-((3-((4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamoyl)-1H-indazol-1-yl)methyl)piperidine-1-carboxylate

According to the procedure for the preparation of Example 329, acylationof Example 342 (10 mg, 0.017 mmol) with methyl choroformate affordedExample 344 (4.7 Example 345 (14.8 mg, 5273% yield). MS(ESI) m/z: 537.3(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.51 (s, 1H), 8.35(d, J=7.4 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.12-8.05 (m, J=8.0 Hz, 2H),7.95-7.87 (m, 3H), 7.78 (d, J=7.7 Hz, 1H), 7.63-7.57 (m, J=7.7 Hz, 2H),7.51 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.3 Hz, 1H), 4.48 (d, J=6.9 Hz, 2H),3.96 (br. s., 2H), 3.57 (s, 3H), 2.73 (br. s., 2H), 2.25 (br. s., 1H),1.47 (br. s., 2H), 1.32-1.19 (m, 2H); HPLC RT=1.83 min (Method F), 1.83min (Method F).

Example 345:1-(2-Hydroxy-2-methylpropyl)-N-(3-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 102 (16 mg, 0.042 mmol) and Intermediate 15 (9.8 mg,0.042 mmol), afforded Example 345 (14.8 mg, 73% yield). MS(ESI) m/z:484.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.75 (br. s., 1H), 10.37 (br.s., 1H), 8.35-8.28 (m, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.90-7.80 (m, 4H),7.70 (d, J=7.2 Hz, 1H), 7.48 (br. s., 1H), 7.40-7.28 (m, 3H), 4.79 (br.s., 1H), 4.49 (br. s., 2H), 3.72 (br. s., 3H), 1.20 (br. s., 6H); HPLCRT=1.65 min (Method E), 1.66 min (Method F).

Example 346:N-(3-Ethoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 103 (14 mg, 0.050 mmol) and Intermediate 15 (11.7 mg,0.050 mmol), afforded Example 346 (22.9 mg, 92% yield). MS(ESI) m/z:498.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.74 (br. s., 1H), 10.35 (br.s., 1H), 8.33-8.27 (m, 1H), 8.24 (d, J=7.7 Hz, 1H), 7.92-7.81 (m, 4H),7.69 (d, J=8.0 Hz, 1H), 7.48 (br. s., 1H), 7.42-7.37 (m, 1H), 7.33 (d,J=7.7 Hz, 2H), 4.77 (br. s., 1H), 4.49 (br. s., 2H), 4.06 (br. s., 2H),1.20 (br. s., 6H), 1.06 (br. s., 3H); HPLC RT=1.76 min (Method E), 1.76min (Method F).

Example 347:N-(3-Ethoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 103 (11 mg, 0.039 mmol) and Intermediate 24 (9.6 mg,0.039 mmol), afforded Example 347 (17.6 mg, 87% yield). MS(ESI) m/z:510.4 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.74 (s, 1H), 10.40 (s, 1H),8.34-8.24 (m, 2H), 7.90 (s, 1H), 7.86-7.82 (m, 3H), 7.71 (dd, J=8.3, 1.7Hz, 1H), 7.53 (ddd, J=8.3, 7.1, 1.1 Hz, 1H), 7.43-7.29 (m, 3H), 4.58 (d,J=7.7 Hz, 2H), 4.14-4.00 (m, 2H), 3.87-3.81 (m, 1H), 3.72-3.64 (m, 2H),3.58 (dd, J=8.8, 5.5 Hz, 1H), 2.96 (s, 1H), 1.94 (s, 1H), 1.72 (d, J=7.4Hz, 1H), 1.06 (t, J=7.0 Hz, 3H); HPLC RT=1.81 min (Method E), 1.81 min(Method F).

Example 348:N-(3-Methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 102 (15 mg, 0.039 mmol) and Intermediate 24 (9.7 mg,0.039 mmol), afforded Example 348 (19.1 mg, 97% yield). MS(ESI) m/z:496.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.79 (br. s., 1H), 10.48 (br.s., 1H), 8.28 (br. s., 2H), 7.90 (d, J=7.2 Hz, 1H), 7.88-7.81 (m, 3H),7.73 (br. s., 1H), 7.53 (br. s., 1H), 7.35 (d, J=8.8 Hz, 3H), 4.58 (br.s., 2H), 3.86 (br. s., 1H), 3.72 (br. s., 3H), 3.68 (br. s., 2H), 3.59(br. s., 1H), 2.96 (br. s., 1H), 1.94 (br. s., 1H), 1.77-1.65 (m, 1H);HPLC RT=1.71 min (Method E), 1.71 min (Method F).

Example 349: Propan-2-yl4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol-1-yl)methyl]piperidine-1-carboxylate

According to the procedure for the preparation of Example 329, acylationof Example 342 (10 mg, 0.017 mmol) with isopropyl chloroformate affordedExample 349 (8 mg, 84% yield). MS(ESI) m/z: 565.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.47 (s, 1H), 8.35 (dd, J=7.7, 1.4 Hz,1H), 8.25 (d, J=8.3 Hz, 1H), 8.13-8.06 (m, J=8.8 Hz, 2H), 7.97-7.85 (m,3H), 7.81-7.73 (m, 1H), 7.63-7.58 (m, J=8.5 Hz, 2H), 7.55-7.48 (m, 1H),7.34 (t, J=7.4 Hz, 1H), 4.75 (quin, J=6.2 Hz, 1H), 4.48 (d, J=7.2 Hz,2H), 4.07-3.93 (m, 2H), 2.82-2.66 (m, 2H), 2.25 (ddd, J=11.1, 7.4, 3.7Hz, 1H), 1.48 (d, J=11.0 Hz, 2H), 1.30-1.22 (m, 2H), 1.20-1.10 (m, 6H);HPLC RT=2.04 min (Method E), 2.04 min (Method F).

Example 350: 2-Fluoroethyl4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol-1-yl)methyl]piperidine-1-carboxylate

According to the procedure for the preparation of Example 329, acylationof Example 342 (10 mg, 0.017 mmol) with 2-fluoroethyl chloroformateafforded Example 350 (8.5 mg, 86% yield). MS(ESI) m/z: 569.2 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 12.82 (br. s., 1H), 10.48 (s, 1H), 8.35 (dd,J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.12-8.05 (m, J=8.5 Hz, 2H),7.96-7.84 (m, 3H), 7.77 (d, J=7.7 Hz, 1H), 7.65-7.56 (m, J=8.5 Hz, 2H),7.55-7.48 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.66-4.61 (m, 1H), 4.55-4.51(m, 1H), 4.49 (d, J=7.2 Hz, 2H), 4.27-4.23 (m, 1H), 4.23-4.15 (m, 1H),3.99 (d, J=13.2 Hz, 2H), 2.77 (br. s., 1H), 2.73 (s, 1H), 2.27 (ddd,J=11.1, 7.4, 3.7 Hz, 1H), 1.51 (d, J=11.0 Hz, 2H), 1.27 (qd, J=12.4, 4.1Hz, 2H); HPLC RT=1.93 min (Method E), 1.95 min (Method F).

Example 351: 2,2,2-Trifluoroethyl4-[(3-{[4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl]carbamoyl}-1H-indazol-1-yl)methyl]piperidine-1-carboxylate

According to the procedure for the preparation of Example 329, acylationof Example 342 (10 mg, 0.017 mmol) with 2,2,2-trifluoroethylchloroformate afforded Example 351 (6.6 mg, 62% yield). MS(ESI) m/z:605.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (br. s., 1H), 10.47 (s,1H), 8.35 (dd, J=7.7, 1.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.13-8.06 (m,J=8.5 Hz, 2H), 7.98-7.85 (m, 3H), 7.81-7.72 (m, 1H), 7.64-7.56 (m, J=8.5Hz, 2H), 7.56-7.48 (m, 1H), 7.34 (t, J=7.6 Hz, 1H), 4.68 (q, J=9.1 Hz,2H), 4.50 (d, J=7.2 Hz, 2H), 3.97 (br. s., 2H), 2.95-2.80 (m, 2H), 2.29(ddt, J=11.2, 7.5, 3.9 Hz, 1H), 1.65-1.47 (m, 2H), 1.28 (qd, J=12.3, 4.3Hz, 2H); HPLC RT=2.02 min (Method E), 2.02 min (Method F).

Example 352:N-(2-Methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 104 (15 mg, 0.056 mmol) and Intermediate 24 (13.8 mg,0.056 mmol), afforded Example 352 (19.4 mg, 68% yield). MS(ESI) m/z:496.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 9.58 (s, 1H),8.55 (d, J=8.3 Hz, 1H), 8.35 (dd, J=7.8, 1.5 Hz, 1H), 8.27 (d, J=8.3 Hz,1H), 7.95-7.88 (m, 3H), 7.86-7.80 (m, 1H), 7.59-7.51 (m, 1H), 7.38 (t,J=7.4 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.25 (dd, J=8.1, 1.8 Hz, 1H),4.65-4.52 (m, 2H), 4.00 (s, 3H), 3.89-3.84 (m, 1H), 3.75 (dd, J=8.5, 6.9Hz, 1H), 3.72-3.66 (m, 1H), 3.59 (dd, J=8.5, 5.8 Hz, 1H), 2.99-2.86 (m,1H), 2.05-1.92 (m, 1H), 1.72 (dd, J=12.9, 6.6 Hz, 1H); HPLC RT=1.82 min(Method E), 1.82 min (Method F).

Example 353:1-(2-Hydroxy-2-methylpropyl)-N-(2-hydroxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 105 (8 mg, 0.032 mmol) and Intermediate 15 (7.4 mg,0.032 mmol), afforded Example 353 (0.9 mg, 6% yield). MS(ESI) m/z: 470.3(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.80 (s, 1H), 9.59 (s, 1H), 8.53(d, J=8.3 Hz, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.26 (d, J=8.3 Hz, 1H),7.98-7.80 (m, 4H), 7.49 (t, J=7.7 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H),7.22-7.16 (m, 1H), 7.11 (dd, J=8.3, 1.4 Hz, 1H), 4.76 (s, 1H), 4.56-4.43(m, 2H), 1.28-1.15 (m, 6H); HPLC RT=1.60 min (Method E), 1.56 min(Method F).

Example 354:N-(2-Hydroxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 105 (16 mg, 0.063 mmol) and Intermediate 24 (15.6 mg,0.063 mmol), afforded Example 354 (4 mg, 13% yield). MS(ESI) m/z: 482.4(M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (s, 1H), 10.63 (s, 1H), 9.59(s, 1H), 8.51 (d, J=8.4 Hz, 1H), 8.37-8.32 (m, 1H), 8.31-8.26 (m, 1H),7.96-7.87 (m, 3H), 7.86-7.80 (m, 1H), 7.54 (ddd, J=8.4, 7.0, 1.1 Hz,1H), 7.44-7.33 (m, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.12 (dd, J=8.3, 1.9 Hz,1H), 4.67-4.54 (m, 2H), 3.95-3.82 (m, 1H), 3.75 (dd, J=8.6, 7.0 Hz, 1H),3.70-3.63 (m, 1H), 3.63-3.50 (m, 1H), 2.96-2.82 (m, 1H), 2.06-1.91 (m,1H), 1.72 (dt, J=13.5, 6.6 Hz, 1H); HPLC RT=9.20 min (Method A), 8.67min (Method B).

Example 355:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

Example 355A: Methyl2-(4-oxo-3,4-dihydrophthalazin-1-yl)-5-(1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamido)benzoate

To a mixture of Intermediate 106 (34 mg, 0.12 mmol), Intermediate 24 (28mg, 0.12 mmol), and HATU (48.2 mg, 0.127 mmol) in DMF (2 mL), was addedDIEA (0.100 mL, 0.58 mmol). The reaction mixture was stirred at rt for16 h, the was concentrated. The residue was purified by preparative HPLCto afford Example 355A (39 mg, 64% yield). MS(ESI) m/z: 524.4 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 10.71 (s, 1H), 8.70 (d, J=2.2 Hz, 1H),8.39-8.31 (m, 1H), 8.28 (td, J=5.5, 2.8 Hz, 2H), 7.90 (d, J=8.5 Hz, 1H),7.88-7.80 (m, 2H), 7.61-7.51 (m, 2H), 7.42-7.34 (m, 1H), 7.32-7.25 (m,1H), 4.68-4.52 (m, 2H), 3.86 (td, J=8.0, 5.6 Hz, 1H), 3.77-3.63 (m, 2H),3.63-3.58 (m, 1H), 3.55 (s, 3H), 3.06-2.92 (m, 1H), 2.03-1.87 (m, 1H),1.78-1.67 (m, 1H).

Example 355

To a solution of Example 355A (13.2 mg, 0.025 mmol) in THF (1 mL) wasadded lithium borohydride (2M in THF, 0.684 mL, 1.37 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 4h, then was diluted with MeOH and DMSO and the solution was purified bypreparative HPLC to afford Example 355 (7.6 mg, 58% yield). MS(ESI) m/z:496.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.40 (s, 1H),8.39-8.30 (m, 1H), 8.26 (d, J=8.3 Hz, 1H), 8.22 (d, J=1.9 Hz, 1H), 7.93(dd, J=8.3, 2.2 Hz, 1H), 7.91-7.83 (m, 3H), 7.55-7.49 (m, 1H), 7.39-7.28(m, 3H), 4.65-4.52 (m, 2H), 4.35 (br. s., 2H), 3.87-3.81 (m, 1H),3.73-3.65 (m, 2H), 3.59 (dd, J=8.8, 5.5 Hz, 1H), 3.04-2.93 (m, 1H),2.04-1.89 (m, 1H), 1.80-1.68 (m, 1H); HPLC RT=1.55 min (Method E), 1.55min (Method F).

Example 356:1-((1-Methylpiperidin-4-yl)methyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 330, reductiveamination of Example 342 (12 mg, 0.021 mmol) afforded Example 356 (6.4mg, 64% yield). MS(ESI) m/z: 493.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.82 (s, 1H), 10.47 (s, 1H), 8.42-8.32 (m, 1H), 8.25 (d, J=8.3 Hz, 1H),8.13-8.05 (m, J=8.5 Hz, 2H), 7.99-7.84 (m, 3H), 7.78 (d, J=8.3 Hz, 1H),7.65-7.55 (m, J=8.8 Hz, 2H), 7.51 (t, J=7.7 Hz, 1H), 7.34 (t, J=7.4 Hz,1H), 4.47 (d, J=7.2 Hz, 2H), 2.83-2.66 (m, 2H), 2.14 (s, 3H), 2.05-1.96(m, 1H), 1.81 (t, J=11.1 Hz, 2H), 1.52-1.30 (m, 4H); HPLC RT=1.30 min(Method E), 1.28 min (Method F).

Example 357:1-(2-Hydroxy-2-methylpropyl)-N-(2-methoxy-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 104 (16 mg, 0.060 mmol) and Intermediate 15 (14 mg,0.060 mmol), afforded Example 357 (6.1 mg, 20% yield). MS(ESI) m/z:484.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 9.59 (s, 1H),8.57 (d, J=8.3 Hz, 1H), 8.35 (dd, J=7.7, 1.4 Hz, 1H), 8.25 (d, J=8.0 Hz,1H), 7.98-7.78 (m, 4H), 7.54-7.46 (m, 1H), 7.39-7.31 (m, 2H), 7.25 (dd,J=8.1, 1.8 Hz, 1H), 4.77 (s, 1H), 4.47 (s, 2H), 3.99 (s, 3H), 1.21 (s,6H); HPLC RT=1.69 min (Method E), 1.70 min (Method F).

Example 358:N-(2-Fluoro-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-3-carboxamide

To a solution of Intermediate 107 (15 mg, 0.041 mmol), Intermediate 15(10.5 mg, 0.045 mmol) and DIEA (0.035 mL, 0.20 mmol) in DMF (1 mL) atrt, was added HATU (17 mg, 0.045 mmol). The mixture was stirred at rtfor 5 days. The reaction mixture was diluted with MeOH (1 mL), then wasfiltered and purified by prep HPLC to afford Example 358 (6.0 mg, 30%yield). MS(ESI) m/z: 472.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (s,1H), 9.85 (s, 1H), 8.29-8.44 (m, 1H), 8.17-8.29 (m, 2H), 7.89-7.99 (m,2H), 7.88 (d, J=8.80 Hz, 1H), 7.78 (d, J=7.43 Hz, 1H), 7.60 (dd, J=1.65,11.28 Hz, 1H), 7.46-7.53 (m, 2H), 7.33 (t, J=7.43 Hz, 1H), 4.48 (s, 2H),1.20 (s, 6H); HPLC RT=1.67 min (Method E), 1.66 min (Method F).

Example 359:1-(2-Hydroxyethyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure of the preparation of Example 355,substituting Intermediate 35 for Intermediate 24 afforded Example 359.MS(ESI) m/z: 456.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.80 (s, 1H),10.45 (s, 1H), 8.36-8.30 (m, 1H), 8.27-8.19 (m, 2H), 7.93-7.84 (m, 3H),7.81 (d, J=8.4 Hz, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.38-7.28 (m, 3H), 4.61(t, J=5.0 Hz, 2H), 4.34 (br. s., 2H), 3.94 (d, J=5.4 Hz, 2H); HPLCRT=1.31 min (Method E), 1.31 min (Method F).

Example 360:1-(2-Hydroxy-2-methylpropyl)-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure of the preparation of Example 355,substituting Intermediate 15 for Intermediate 24 afforded Example 360.MS(ESI) m/z: 484.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.80 (s, 1H),10.39 (s, 1H), 8.38-8.28 (m, 1H), 8.23 (d, J=8.1 Hz, 1H), 8.18 (s, 1H),7.99-7.80 (m, 4H), 7.48 (t, J=7.6 Hz, 1H), 7.38-7.20 (m, 3H), 5.17 (t,J=5.4 Hz, 1H), 4.84 (s, 1H), 4.48 (s, 2H), 4.34 (br. s., 2H), 3.89 (s,1H), 1.19 (s, 6H); HPLC RT=1.39 min (Method E), 1.40 min (Method F).

Example 361:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (12.5 mg, 0.047 mmol) and Intermediate 15 (14 mg,0.051 mmol), afforded Example 361 (13.4 mg, 53% yield). MS(ESI) m/z:484.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.40 (s, 1H),8.34-8.29 (m, 1H), 8.28-8.19 (m, 2H), 7.97-7.80 (m, 4H), 7.52 (td,J=7.7, 1.1 Hz, 1H), 7.40-7.27 (m, 3H), 5.11 (t, J=5.4 Hz, 1H), 4.61 (t,J=7.4 Hz, 2H), 4.34 (br. s., 2H), 3.85-3.79 (m, 2H), 3.29-3.19 (m, 3H),1.96-1.85 (m, 2H); HPLC RT=1.63 min (Method E), 1.64 min (Method F).

Example 362:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (13 mg, 0.049 mmol) andpyrazolo[1,5-a]pyridine-3-carboxylic acid (7.9 mg, 0.049 mmol), affordedExample 362 (4.1 mg, 20% yield). MS(ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.78 (br. s., 1H), 10.16 (br. s., 1H), 8.90-8.77 (m,2H), 8.43-8.24 (m, 2H), 8.04 (br. s., 1H), 7.96-7.81 (m, 3H), 7.55 (t,J=7.5 Hz, 1H), 7.39-7.26 (m, 2H), 7.14 (t, J=6.4 Hz, 1H), 4.33 (br. s.,2H); HPLC RT=1.28 min (Method E), 1.16 min (Method F).

Example 363:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-methyl-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (8 mg, 0.030 mmol) and1-methyl-1H-indazole-3-carboxylic acid (5.3 mg, 0.030 mmol), affordedExample 363 (7 mg, 55% yield). MS(ESI) m/z: 426.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.77 (s, 1H), 10.49 (s, 1H), 8.37-8.29 (m, 1H),8.28-8.20 (m, 2H), 7.92-7.83 (m, 3H), 7.80 (d, J=8.5 Hz, 1H), 7.53 (ddd,J=8.4, 7.0, 1.1 Hz, 1H), 7.41-7.25 (m, 3H), 5.10 (t, J=5.4 Hz, 1H), 4.34(br. s., 2H), 4.23 (s, 3H); HPLC RT=1.40 min (Method E), 1.41 min(Method F).

Example 364:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-isopropyl-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (8 mg, 0.030 mmol) and1-isopropyl-1H-indazole-3-carboxylic acid (6.1 mg, 0.030 mmol), affordedExample 364 (6.9 mg, 51% yield). MS(ESI) m/z: 454.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.78 (s, 1H), 10.25 (s, 1H), 8.37-8.30 (m, 1H), 8.25(d, J=8.0 Hz, 1H), 8.19 (d, J=1.9 Hz, 1H), 8.01-7.92 (m, 1H), 7.91-7.83(m, 3H), 7.50 (td, J=7.7, 0.8 Hz, 1H), 7.38-7.28 (m, 3H), 5.25-5.06 (m,2H), 4.35 (br. s., 2H), 1.62 (d, J=6.6 Hz, 6H); HPLC RT=1.81 min (MethodE), 1.69 min (Method F).

Example 365:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (10 mg, 0.037 mmol) andimidazo[1,2-a]pyridine-3-carboxylic acid (6.7 mg, 0.041 mmol), affordedExample 365 (10.7 mg, 68% yield). MS(ESI) m/z: 412.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 9.51 (d, J=7.0 Hz, 1H), 8.66 (s, 1H), 8.41-8.23 (m, 1H),8.05 (s, 1H), 7.93 (s, 1H), 7.92-7.83 (m, 3H), 7.78 (d, J=8.9 Hz, 1H),7.54 (t, J=7.8 Hz, 1H), 7.32 (d, J=7.9 Hz, 2H), 7.21 (t, J=6.7 Hz, 1H),4.34 (br. s., 2H), 3.11 (d, J=7.3 Hz, 1H); HPLC RT=0.95 min (Method E),1.14 min (Method F).

Example 366:5-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (10 mg, 0.037 mmol) and Intermediate 49 (10.9 mg,0.041 mmol), afforded Example 366 (8.6 mg, 45% yield). MS(ESI) m/z:514.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.43 (s, 1H), 8.32 (d, J=5.2Hz, 1H), 8.15 (s, 1H), 7.99-7.77 (m, 6H), 7.42 (t, J=9.0 Hz, 1H),7.36-7.26 (m, 2H), 4.54 (d, J=7.3 Hz, 2H), 4.33 (br. s., 2H), 3.91-3.76(m, 1H), 3.61-3.51 (m, 1H), 2.99-2.90 (m, 1H), 1.99-1.88 (m, 1H), 1.69(dq, J=12.7, 6.6 Hz, 1H); HPLC RT=1.52 min (Method E), 1.48 min (MethodF).

Example 367:N-(3-(Hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-2-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (9.5 mg, 0.036 mmol) and Intermediate 109 (9.6 mg,0.039 mmol), afforded Example 367 (13.7 mg, 74% yield). MS(ESI) m/z:496.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.46 (s, 1H), 8.41-8.30 (m,1H), 8.29-8.18 (m, 2H), 8.00-7.78 (m, 4H), 7.50 (t, J=7.6 Hz, 1H),7.38-7.26 (m, 3H), 4.62 (d, J=5.4 Hz, 2H), 4.41 (quin, J=6.1 Hz, 1H),4.34 (br. s., 2H), 3.73 (q, J=6.8 Hz, 1H), 3.68-3.56 (m, 1H), 3.44-3.33(m, 1H), 2.08-1.94 (m, 1H), 1.86-1.71 (m, 3H); HPLC RT=1.54 min (MethodE), 1.66 min (Method F).

Example 368:6-Fluoro-N-(3-(hydroxymethyl)-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 108 (9.5 mg, 0.036 mmol) and Intermediate 50 (10.3 mg,0.039 mmol), afforded Example 368 (8.6 mg, 47% yield). MS(ESI) m/z:514.2 (M+H)⁺; (500 MHz, DMSO-d₆) δ 10.47 (s, 1H), 8.39-8.30 (m, 1H),8.30-8.17 (m, 2H), 7.96-7.77 (m, 4H), 7.39-7.31 (m, 2H), 7.24 (t, J=8.9Hz, 1H), 4.63-4.49 (m, 2H), 4.34 (br. s., 2H), 3.88-3.80 (m, 1H),3.76-3.64 (m, 2H), 3.58 (dd, J=8.6, 5.6 Hz, 1H), 2.95 (dt, J=13.7, 6.8Hz, 1H), 2.07-1.89 (m, 1H), 1.71 (dq, J=12.9, 6.6 Hz, 1H); HPLC RT=1.55min (Method E), 1.76 min (Method F).

Example 369:1-(2-Hydroxy-2-methylpropyl)-N-(4-(6-methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-indazole-3-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 110 (15 mg, 0.039 mmol) and Intermediate 15 (11 mg,0.047 mmol), afforded Example 369 (0.9 mg, 6% yield). MS(ESI) m/z: 484.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.75 (s, 1H), 10.40 (s, 1H),8.23 (d, J=8.3 Hz, 1H), 8.06 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 1H),7.76-7.69 (m, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.53-7.42 (m, 2H), 7.32 (t,J=7.6 Hz, 1H), 4.79 (s, 1H), 4.49 (s, 2H), 3.97 (s, 3H), 1.20 (s, 6H);HPLC RT=1.76 min (Method E), 1.64 min (Method F).

Example 370:N-(4-(6-Methoxy-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)imidazo[1,2-a]pyridine-2-carboxamide

According to the procedure for the preparation of Example 45, couplingof Intermediate 110 (15 mg, 0.039 mmol) and Intermediate 15 (7.7 mg,0.047 mmol), afforded Example 370 (0.5 mg, 3% yield). MS(ESI) m/z: 412.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.74 (s, 1H), 10.51 (s, 1H),8.64 (d, J=6.6 Hz, 1H), 8.57 (s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.76-7.64(m, 3H), 7.56 (d, J=8.5 Hz, 2H), 7.49 (dd, J=9.1, 2.8 Hz, 1H), 7.43-7.36(m, 1H), 7.04 (t, J=6.7 Hz, 1H), 3.96 (s, 3H); HPLC RT=1.18 min (MethodE), 1.37 min (Method F).

Example 371:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)spiro[indoline-3,4′-piperidine]-1-carboxamide

2-(4-Isocyanatophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (50 mg,0.204 mmol) and tert-butylspiro[indoline-3,4′-piperidine]-1′-carboxylate (58.8 mg, 0.204 mmol)were dissolved in THF (3 mL), and DIEA (0.053 mL, 0.31 mmol) was added.The reaction mixture was stirred at rt for 1 h. THF was removed underreduced pressure. To the obtained residue were added4-chlorophthalazin-1(2H)-one (18.4 mg, 0.102 mmol) and phosphoric acid,potassium salt (54.1 mg, 0.255 mmol), followed by dioxane (3 mL) andwater (0.333 mL). The mixture was degassed (evacuated and flushed withAr (3×)). Pd(PPh₃)₄ (11.8 mg, 10.2 μmol) was added, then the mixture wasdegassed (2×). The reaction vial was sealed and heated in a microwavereactor at 150° C. for 30 min. The solvent was removed under reducedpressure, and the residue was treated with TFA (2 mL). The reactionmixture was stirred for 15 min. TFA was removed under reduced pressure.The residue was purified by prep HPLC to afford Example 371 (11.9 mg,25% yield). MS(ESI) m/z: 452.3 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 8.90 (br. s., 1H), 8.81 (s, 1H), 8.35 (d, J=7.4 Hz, 1H),8.02-7.85 (m, 4H), 7.76 (d, J=8.4 Hz, 3H), 7.55 (d, J=8.4 Hz, 2H), 7.23(t, J=7.7 Hz, 1H), 7.18 (d, J=7.4 Hz, 1H), 7.06-6.95 (m, 1H), 4.18 (s,2H), 3.48-3.33 (m, 1H), 3.02 (br. s., 2H), 2.11-1.99 (m, 2H), 1.88 (d,J=13.8 Hz, 2H); HPLC RT=1.13 min (Method E), 1.09 min (Method F).

Example 372:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(piperidin-4-yl)-1H-1,2,3-triazole-4-carboxamide

To a mixture of Intermediate 12 (20 mg, 0.084 mmol),1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-1,2,3-triazole-4-carboxylicacid (25 mg, 0.084 mmol), HATU (38.5 mg, 0.101 mmol) in DMF (1.5 mL),was added DIEA (0.074 mL, 0.42 mmol). The mixture was stirred rt for 16h, then was concentrated. The residue was stirred with TFA (0.5 mL) inDCM (1 mL) for 30 min, then was concentrated and purified by prep HPLCto afford Example 372 (9.6 mg, 27% yield). MS(ESI) m/z: 416.2 (M+H)⁺; ¹HNMR (500 MHz, DMSO-d₆) δ 12.88-12.81 (m, 1H), 10.71 (s, 1H), 8.88 (s,1H), 8.34 (d, J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.95-7.85 (m, 2H),7.75 (d, J=7.1 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 4.94 (br. s., 1H), 3.46(d, J=12.1 Hz, 1H), 3.18-3.04 (m, 2H), 2.38 (d, J=12.8 Hz, 2H), 2.23 (d,J=10.8 Hz, 2H); HPLC RT=0.78 min (Method E), 0.75 min (Method F).

Example 373:1-Cyclohexyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry MeCN (1.5 mL),then bromocyclohexane (0.072 mL, 0.588 mmol) was added, followed bycesium carbonate (96 mg, 0.294 mmol) and the reaction mixture was heatedunder microwave irradiation at 150° C. for 30 min. The reaction mixturewas cooled to rt, and most of MeCN was removed under reduced pressure.The obtained residue was treated TFA (2 mL), and the reaction mixturewas stirred at rt for 15 min. TFA was removed under reduced pressure.The crude product was purified by preparative HPLC to afford 17.6 mg(57%) of Example 373. MS(ESI) m/z: 414.2 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.81 (s, 1H), 10.01 (s, 1H), 8.40 (s, 1H), 8.36-8.30 (m,1H), 8.05 (s, 1H), 7.93-7.84 (m, 4H), 7.75 (d, J=7.6 Hz, 1H), 7.56 (d,J=8.5 Hz, 2H), 4.27-4.14 (m, 1H), 2.10-2.00 (m, 2H), 1.82 (d, J=13.4 Hz,2H), 1.77-1.60 (m, 3H), 1.41 (q, J=12.9 Hz, 2H), 1.22 (q, J=13.0 Hz,1H); HPLC RT=1.61 min (Method E), 1.62 min (Method F).

Example 374:1-Cyclopentyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting bromocyclopentane for bromocyclohexane afforded Example374. MS(ESI) m/z: 400.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.82(s, 1H), 10.04 (s, 1H), 8.39 (s, 1H), 8.35-8.31 (m, 1H), 8.04 (s, 1H),7.94-7.88 (m, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.3 Hz, 1H), 7.55(d, J=8.5 Hz, 2H), 4.74 (quin, J=6.9 Hz, 1H), 2.17-2.05 (m, 2H), 1.91(dd, J=12.8, 7.0 Hz, 2H), 1.84-1.74 (m, 2H), 1.71-1.60 (m, 2H); HPLCRT=1.50 min (Method E), 1.51 min (Method F).

Example 375:1-(Cyclopropylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting (bromomethyl)cyclopropane for bromocyclohexane affordedExample 375. MS(ESI) m/z: 386.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.82 (s, 1H), 10.08 (s, 1H), 8.40 (s, 1H), 8.33 (d, J=7.0 Hz, 1H), 8.06(s, 1H), 7.95-7.82 (m, 4H), 7.74 (d, J=7.3 Hz, 1H), 7.55 (d, J=8.2 Hz,2H), 4.02 (d, J=7.3 Hz, 2H), 1.32-1.22 (m, 1H), 0.59-0.52 (m, 2H),0.42-0.34 (m, 2H); HPLC RT=1.36 min (Method E), 1.36 min (Method F).

Example 376:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting 2,2,2-trifluoroethyl trifluoromethanesulfonate forbromocyclohexane afforded Example 376. MS(ESI) m/z: 386.2 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 12.83 (s, 1H), 10.23 (s, 1H), 8.50 (s, 1H),8.33 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 7.95-7.82 (m, 4H), 7.74 (d, J=7.6Hz, 1H), 7.56 (d, J=8.2 Hz, 2H), 5.20 (q, J=9.1 Hz, 2H); HPLC RT=1.34min (Method E), 1.35 min (Method F).

Example 377:1-(2-Hydroxy-2-methylpropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2,2-dimethyloxirane for bromocyclohexane afforded Example377. MS(ESI) m/z: 404.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.84(s, 1H), 10.10 (s, 1H), 8.36-8.28 (m, 2H), 8.05 (s, 1H), 7.95-7.84 (m,4H), 7.75 (d, J=7.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 4.91 (s, 1H), 4.07(s, 2H), 1.08 (s, 6H); HPLC RT=0.98 min (Method E), 0.98 min (Method F).

Example 378:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2-(trifluoromethyl)oxirane for bromocyclohexane affordedExample 378. MS(ESI) m/z: 440.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.36-8.30 (m, 1H), 8.14 (s,1H), 7.99-7.84 (m, 5H), 7.75 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H),4.53-4.40 (m, 2H), 4.39-4.27 (m, 1H); HPLC RT=1.11 min (Method E), 1.11min (Method F).

Example 379:1-(2-Hydroxy-3-methoxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2-(methoxymethyl)oxirane for bromocyclohexane affordedExample 379. MS(ESI) m/z: 420.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm10.07 (s, 1H), 8.38-8.29 (m, 2H), 8.06 (s, 1H), 7.96-7.84 (m, 4H), 7.75(d, J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H), 4.23 (dd, J=13.8, 3.7 Hz,1H), 4.13-4.04 (m, 1H), 3.98 (br. s., 1H), 3.31-3.25 (m, 5H); HPLCRT=0.91 min (Method E), 1.00 min (Method F).

Example 380:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2,2-bis(trifluoromethyl)oxirane for bromocyclohexaneafforded Example 380. MS(ESI) m/z: 512.2 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.83 (s, 1H), 10.17 (s, 1H), 8.40 (s, 1H), 8.33 (d,J=7.3 Hz, 1H), 8.11 (s, 1H), 7.97-7.81 (m, 4H), 7.74 (d, J=7.6 Hz, 1H),7.56 (d, J=7.9 Hz, 2H), 4.81 (s, 2H); HPLC RT=1.48 min (Method E), 1.50min (Method F).

Example 381:1-(tert-Butyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

Intermediate 111 (25 mg, 0.059 mmol) was suspended in dry MeCN (1.5 mL),then 2-bromo-2-methylpropane (0.066 mL, 0.59 mmol) was added, followedby silver carbonate (81 mg, 0.29 mmol) and the reaction mixture stirredat 150° C. for 15 min under microwave irradiation. The reaction mixturewas cooled to rt, and most of MeCN was removed under reduced pressure.The obtained residue was treated with TFA (2 mL), and the reactionmixture was stirred at rt for 15 min. TFA was removed under reducedpressure, the residue was diluted with DMF (2 mL), filtered and purifiedby prep HPLC to afford Example 381 (2.6 mg, 11% yield). MS(ESI) m/z:388.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.82 (s, 1H), 10.03 (s,1H), 8.46 (s, 1H), 8.33 (d, J=7.9 Hz, 1H), 8.05 (s, 1H), 7.95-7.88 (m,2H), 7.86 (d, J=8.5 Hz, 2H), 7.74 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.5 Hz,2H), 1.55 (s, 9H); HPLC RT=1.42 min (Method E), 1.44 min (Method F).

Example 382:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-propyl-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting 1-bromopropane for bromocyclohexane afforded Example 382.MS(ESI) m/z: 374.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.82 (s,1H), 10.09 (s, 1H), 8.32 (s, 2H), 8.05 (s, 1H), 7.94-7.87 (m, 2H), 7.85(d, J=8.2 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.54 (d, J=8.2 Hz, 2H), 4.10(t, J=6.9 Hz, 2H), 1.79 (sxt, J=7.2 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H);HPLC RT=1.30 min (Method E), 1.32 min (Method F).

Example 383:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,3,3-tetrafluoropropyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate forbromocyclohexane afforded Example 383. MS(ESI) m/z: 446.1 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 12.83 (s, 1H), 10.22 (s, 1H), 8.46 (s, 1H),8.33 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.95-7.87 (m, 2H), 7.85 (d, J=8.5Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 6.73-6.25 (m,1H), 4.99 (t, J=15.0 Hz, 2H); HPLC RT=1.40 min (Method E), 1.40 min(Method F).

Example 384:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 4-bromotetrahydro-2H-pyran for bromocyclohexane affordedExample 384. MS(ESI) m/z: 416.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.81 (s, 1H), 10.01 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.10(s, 1H), 7.98-7.85 (m, 4H), 7.76 (d, J=7.6 Hz, 1H), 7.57 (d, J=8.2 Hz,2H), 4.49 (t, J=11.3 Hz, 1H), 3.98 (d, J=10.1 Hz, 2H), 3.49 (t, J=11.4Hz, 1H), 2.10-1.89 (m, 4H); HPLC RT=1.22 min (Method E), 1.22 min(Method F).

Example 385:1-(Cyclopropylmethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting bromocyclobutane for bromocyclohexane afforded Example 385.MS(ESI) m/z: 386.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.81 (s,1H), 10.02 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.3 Hz, 1H), 8.09 (s, 1H),7.94-7.84 (m, 4H), 7.75 (d, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 2H), 4.90(quin, J=8.3 Hz, 1H), 2.49-2.37 (m, 4H), 1.87-1.76 (m, 2H); HPLC RT=1.39min (Method E), 1.39 min (Method F).

Example 386:1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2,2-difluoroethyl trifluoromethanesulfonate forbromocyclohexane afforded Example 386. MS(ESI) m/z: 396.2 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 12.83 (s, 1H), 10.14 (s, 1H), 8.46 (s, 1H),8.34 (d, J=7.1 Hz, 1H), 8.16 (s, 1H), 7.97-7.85 (m, 4H), 7.76 (d, J=7.4Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.42 (t, J=54.2 Hz, 1H), 4.73 (td,J=15.2, 3.2 Hz, 2H); HPLC RT=1.17 min (Method E), 1.17 min (Method F).

Example 387:1-(2-Hydroxypropyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 2-methyloxirane for bromocyclohexane afforded Example 387.MS(ESI) m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.83 (s,1H), 10.06 (s, 1H), 8.37-8.31 (m, 2H), 8.06 (s, 1H), 7.95-7.86 (m, 4H),7.75 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H), 5.06 (d, J=4.7 Hz, 1H),4.15-4.08 (m, 1H), 4.07-3.95 (m, 2H), 1.07 (d, J=6.1 Hz, 3H); HPLCRT=0.99 min (Method E), 0.99 min (Method F).

Example 388:1-(4-Chlorophenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

Intermediate 111 (20 mg, 0.047 mmol), 1-chloro-4-iodobenzene (34 mg,0.141 mmol), salicylaldoxime (6.5 mg, 0.047 mmol) and cesium carbonate(46 mg, 0.14 mmol) were suspended in DMF (1.5 mL). The obtainedsuspension was degassed (3× vacuum/Ar), then copper(I) oxide (1.7 mg,0.012 mmol) was added. The reaction mixture was degassed again (2×vacuum/Ar) and was stirred under microwave irradiation at 200° C. for 30min. The reaction mixture was cooled to rt, and most of DMF wasevaporated. The obtained residue was treated TFA (2 mL), and thereaction mixture was stirred at rt for 15 min. TFA was removed underreduced pressure, the residue was purified by prep HPLC to affordExample 388 (2.2 mg, 10% yield). MS(ESI) m/z: 442.2 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.82 (s, 1H), 10.22 (s, 1H), 9.13 (s, 1H), 8.37 (s,1H), 8.34 (d, J=7.6 Hz, 1H), 8.02-7.84 (m, 6H), 7.76 (d, J=7.6 Hz, 1H),7.61 (dd, J=13.9, 8.4 Hz, 4H); HPLC RT=1.77 min (Method E), 1.76 min(Method F).

Example 389:1-(Oxetan-3-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 3-bromooxetane for bromocyclohexane afforded Example 389.MS(ESI) m/z: 388.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.84 (s,1H), 10.12 (s, 1H), 8.54 (s, 1H), 8.37-8.30 (m, 1H), 8.21 (s, 1H),7.96-7.85 (m, 4H), 7.75 (d, J=7.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 5.65(quin, J=6.9 Hz, 1H), 5.00-4.93 (m, 2H), 4.93-4.87 (m, 2H); HPLC RT=1.03min (Method E), 0.94 min (Method F).

Example 390:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 3-bromotetrahydrofuran for bromocyclohexane affordedExample 390. MS(ESI) m/z: 402.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 10.07 (s, 1H), 8.45 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.09(s, 1H), 7.97-7.85 (m, 4H), 7.75 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.1 Hz,2H), 5.10 (br. s., 1H), 4.06-3.97 (m, 2H), 3.97-3.90 (m, 1H), 3.88-3.78(m, 1H), 2.48-2.36 (m, 1H), 2.27 (d, J=3.7 Hz, 1H); HPLC RT=1.10 min(Method E), 1.02 min (Method F).

Example 391:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

Intermediate 111 (20 mg, 0.047 mmol) was treated with TFA (2 mL). Thereaction mixture was stirred at rt for 15 min. TFA was removed underreduced pressure, then the residue was purified by prep HPLC to affordExample 391 (11.6 mg, 53% yield). MS(ESI) m/z: 332.0 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.81 (s, 1H), 10.02 (s, 1H), 8.41 (br. s., 1H),8.34 (d, J=7.3 Hz, 1H), 8.10 (br. s., 1H), 7.96-7.84 (m, 4H), 7.76 (d,J=7.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 2H); HPLC RT=1.01 min (Method E), 1.01min (Method F).

Example 392:1-(Bicyclo[2.2.1]heptan-7-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamideExample 393:1-((1S,2S,4R)-Bicyclo[2.2.1]heptan-2-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide

Intermediate 111 (20 mg, 0.047 mmol) was suspended in dry MeCN (1.5 mL),then (1R,4S)-7-bromobicyclo[2.2.1]heptane (0.060 mL, 0.470 mmol) wasadded, followed by cesium carbonate (153 mg, 0.470 mmol) and thereaction mixture was heated under microwave irradiation at 150° C. for15 min. The reaction mixture was heated at 175° C. for 30 min (3×). Thereaction mixture was cooled to rt, and most of MeCN was removed underreduced pressure. The obtained residue was treated TFA (2 mL), and thereaction mixture was stirred at rt for 15 min. TFA was removed underreduced pressure, the residue was purified by prep HPLC to affordExample 392 (7.8 mg, 38% yield) and Example 393 (2.5 mg, 13% yield).

Example 392

MS(ESI) m/z: 426.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.81 (s,1H), 9.98 (s, 1H), 8.46 (s, 1H), 8.34 (d, J=7.6 Hz, 1H), 8.04 (s, 1H),7.98-7.87 (m, 4H), 7.76 (d, J=7.3 Hz, 1H), 7.56 (d, J=8.2 Hz, 2H),4.38-4.29 (m, 1H), 2.47 (br. s., 1H), 2.39 (br. s., 1H), 2.05 (d, J=13.4Hz, 1H), 1.91-1.83 (m, 1H), 1.75 (d, J=9.8 Hz, 1H), 1.65-1.46 (m, 2H),1.38-1.30 (m, 1H), 1.21 (d, J=9.2 Hz, 2H); HPLC RT=1.51 min (Method E),1.52 min (Method F).

Example 393

MS(ESI) m/z: 426.0 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.81 (br.s., 1H), 9.99 (br. s., 1H), 8.51-8.40 (m, 1H), 8.34 (d, J=7.0 Hz, 1H),8.07 (br. s., 1H), 7.89 (d, J=7.9 Hz, 4H), 7.76 (d, J=7.0 Hz, 1H), 7.57(d, J=7.3 Hz, 2H), 4.73 (br. s., 1H), 2.34 (br. s., 1H), 2.08 (d, J=14.3Hz, 1H), 1.90 (br. s., 1H), 1.78 (br. s., 1H), 1.65-1.47 (m, 2H),1.46-1.27 (m, 4H); HPLC RT=1.49 min (Method E), 1.49 min (Method F).

Example 394:5-Methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-phenyl-1H-pyrazole-4-carboxamide

Intermediate 94 (50 mg, 0.137 mmol) was dissolved in dry DMF (2 mL),then 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (55.4 mg, 0.274mmol) and DIEA (0.143 mL, 0.821 mmol) were added. After stirring for 5min at rt, HATU (52 mg, 0.137 mmol) was added, and the reaction mixturewas stirred at 60° C. for 4 h. The reaction mixture was quenched withMeOH (0.1 mL) was purified by preparative HPLC to afford Example 394 (18mg, 29% yield) as an off-white solid. MS(ESI) m/z: 436.0 (M+H)⁺; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 12.78 (s, 1H), 9.97 (s, 1H), 8.37 (s, 1H),8.35-8.29 (m, 1H), 7.91-7.84 (m, 2H), 7.79 (d, J=1.8 Hz, 1H), 7.74 (dd,J=8.4, 2.0 Hz, 1H), 7.63-7.54 (m, 4H), 7.54-7.46 (m, 1H), 7.32-7.26 (m,2H), 2.58 (s, 3H), 2.09 (s, 3H); HPLC RT=8.43 min (Method A), 8.11 min(Method B).

Example 395:5-(tert-Butyl)-1-methyl-N-(3-methyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide

According to the procedure for the preparation of Example 394, couplingof Intermediate 94 (40 mg, 0.109 mmol) with5-(tert-butyl)-1-methyl-1H-pyrazole-3-carboxylic acid (31.9 mg, 0.175mmol) 60° C. for 2 days afforded Example 395 (18.2 mg, 39% yield).MS(ESI) m/z: 416.1 (M+H)⁺; ¹H NMR ¹H-NMR: (500 MHz, DMSO-d₆) δ ppm 12.77(s, 1H), 10.00 (s, 1H), 8.35-8.29 (m, 1H), 7.91-7.83 (m, 3H), 7.79 (dd,J=8.4, 2.0 Hz, 1H), 7.31-7.24 (m, 2H), 6.59 (s, 1H), 4.05 (s, 3H), 2.07(s, 3H), 1.39 (s, 9H); HPLC RT=13.24 min (Method A), 11.79 min (MethodB).

Example 396:1-(1,1-Dioxidotetrahydrothiophen-3-yl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-4-carboxamide,TFA

According to the procedure for the preparation of Example 373,substituting 3-bromotetrahydrothiophene 1,1-dioxide for bromocyclohexaneafforded Example 396. MS(ESI) m/z: 450.1 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.81 (s, 1H), 10.09 (s, 1H), 8.54 (s, 1H), 8.34 (d,J=7.3 Hz, 1H), 8.19 (s, 1H), 7.98-7.84 (m, 4H), 7.76 (d, J=7.6 Hz, 1H),7.58 (d, J=7.9 Hz, 2H), 5.35 (t, J=7.3 Hz, 1H), 3.78 (dd, J=13.6, 8.4Hz, 1H), 3.51 (dd, J=13.9, 7.5 Hz, 1H), 3.49-3.38 (m, 1H), 2.73-2.65 (m,1H), 2.64-2.55 (m, 1H); HPLC RT=1.13 min (Method E), 1.14 min (MethodF).

Example 397:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(pyrrolidin-3-yl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting tert-butyl 3-bromopyrrolidine-1-carboxylate forbromocyclohexane afforded Example 397. MS(ESI) m/z: 401.3 (M+H)⁺; ¹H NMR(500 MHz, DMSO-d₆) δ ppm 10.09 (s, 1H), 8.45 (s, 1H), 8.34 (d, J=7.1 Hz,1H), 8.09 (s, 1H), 7.95-7.83 (m, 5H), 7.74 (d, J=7.4 Hz, 1H), 7.56 (d,J=8.4 Hz, 2H), 4.96 (br. s., 1H), 3.29 (dd, J=12.1, 7.1 Hz, 1H),3.17-3.06 (m, 2H), 3.03-2.93 (m, 1H), 2.32-2.22 (m, 1H), 2.15-2.01 (m,1H); HPLC RT=0.85 min (Method E), 0.85 min (Method F).

Example 398:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3,3,3-trifluoropropyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 3-bromo-1,1,1-trifluoropropane for bromocyclohexaneafforded Example 398. MS(ESI) m/z: 428.2 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.84 (s, 1H), 10.11 (s, 1H), 8.44 (s, 1H), 8.34 (d,J=7.1 Hz, 1H), 8.13 (s, 1H), 7.95-7.83 (m, 4H), 7.75 (d, J=7.7 Hz, 1H),7.56 (d, J=8.4 Hz, 2H), 4.46 (t, J=6.6 Hz, 2H), 2.98-2.89 (m, 2H); HPLCRT=1.35 min (Method E), 1.35 min (Method F).

Example 399:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(3-(pyrrolidin-1-yl)propyl)-1H-pyrazole-4-carboxamide

According to the procedure for the preparation of Example 373,substituting 1-(3-bromopropyl)pyrrolidine, HCl for bromocyclohexaneafforded Example 399. MS(ESI) m/z: 443.3 (M+H)⁺; ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.83 (s, 1H), 10.02 (s, 1H), 8.39 (s, 1H), 8.34 (d,J=7.1 Hz, 1H), 8.08 (s, 1H), 7.97-7.85 (m, 4H), 7.76 (d, J=8.1 Hz, 1H),7.57 (d, J=8.4 Hz, 2H), 4.21 (t, J=6.9 Hz, 2H), 2.43 (br. s., 4H), 2.37(t, J=7.1 Hz, 2H), 1.97 (quin, J=6.9 Hz, 2H), 1.69 (br. s., 4H); HPLCRT=0.91 min (Method E), 0.90 min (Method F).

Example 400:5-Methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide

To a mixture of Intermediate 12 (15 mg, 0.043 mmol), Intermediate 112(9.5 mg, 0.047 mmol), and HATU (18 mg, 0.047 mmol) in DMF (1.5 mL), wasadded DIEA (0.037 mL, 0.21 mmol). The mixture was stirred rt for 3 h,then 50° C. overnight. The mixture was purified by prep PHLC to affordExample 400 (4.6 mg, 24% yield). MS(ESI) m/z: 423.1 (M+H)⁺; ¹H NMR (500MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.73 (s, 1H), 8.35 (d, J=6.7 Hz, 1H),8.09-8.03 (m, J=7.9 Hz, 2H), 7.97-7.87 (m, 2H), 7.76 (d, J=7.3 Hz, 1H),7.67 (br. s., 5H), 7.61-7.55 (m, J=7.9 Hz, 2H), 2.60 (s, 3H); HPLCRT=1.70 min (Method E), 1.71 min (Method F).

Example 401:1-(4-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

According to the procedure for the preparation of Example 400, couplingof Intermediate 12 (12 mg, 0.034 mmol) and Intermediate 113 (8.8 mg,0.038 mmol) afforded Example 401 (1.8 mg, 11% yield). MS(ESI) m/z: 453.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.70 (s, 1H), 8.34(d, J=7.6 Hz, 1H), 8.05 (d, J=7.9 Hz, 2H), 7.91 (t, J=7.6 Hz, 2H), 7.76(d, J=7.9 Hz, 1H), 7.58 (d, J=8.2 Hz, 4H), 7.19 (d, J=8.2 Hz, 2H), 3.86(s, 3H), 2.56 (s, 3H); HPLC RT=1.69 min (Method E), 1.70 min (Method F).

Example 402:1-(4-Methoxyphenyl)-4-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2,3-triazole-5-carboxamide

According to the procedure for the preparation of Example 400, couplingof Intermediate 12 (12 mg, 0.034 mmol) and Intermediate 114 (8.8 mg,0.038 mmol) afforded Example 402 (2.5 mg, 16% yield). MS(ESI) m/z: 453.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.83 (s, 1H), 10.98 (s, 1H), 8.33(d, J=7.6 Hz, 1H), 7.89 (d, J=4.3 Hz, 2H), 7.76 (d, J=7.9 Hz, 2H), 7.70(d, J=7.0 Hz, 1H), 7.58 (d, J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.11(d, J=8.5 Hz, 2H), 3.80 (s, 3H), 2.45 (s, 3H); HPLC RT=1.44 min (MethodE), 1.45 min (Method F).

Example 403:5-(Difluoromethoxy)-1-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide

Example 403A: Methyl5-(difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylate

Methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (J. Med. Chem.,54:8174 (2011)) (0.35 g, 2.24 mmol), K₂CO₃ (0.62 g, 4.48 mmol), andsodium chlorodifluoroacetate (0.684 g, 4.48 mmol) were dissolved in DMF(10 ml) and water (1 ml). The reaction was heated to 130° C. for 20 min.The reaction was diluted with water (100 mL) and EtOAc (200 mL). Theorganic phase was separated, washed with water (5×), brine and dried(Na₂SO₄). EtOAc was removed under reduced pressure and the residue waspurified by flash chromatography: (40 g) 0-80% EtOAc/Hex. Fractions werecombined and concentrated under reduced pressure to give Example 403A(0.373 g, 81% yield) as a colorless syrup. MS(ESI) m/z: 207.0 (M+H)⁺;¹H-NMR: (400 MHz, CDCl₃) δ ppm 6.44 (t, J=1.0 Hz, 1H), 6.46 (t, J=72.2Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H); ¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm−84.02 (s, 2F).

Example 403B: 5-(Difluoromethoxy)-1-methyl-1H-pyrazole-3-carboxylic acid

Example 403A (0.373 g, 1.809 mmol) was dissolved in THF (7.5 ml) andMeOH (1.5 ml), then LiOH (1 M in water) (5.43 ml, 5.43 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.418 ml, 5.43 mmol), and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water and was purifiedby preparative HPLC. Fractions were combined and concentrated to affordExample 403B (0.230 g, 66% yield) as a white solid. MS(ESI) m/z: 192.9(M+H)⁺; ¹H-NMR: (500 MHz, DMSO-d₆) δ ppm 7.30 (t, J=70.4 Hz, 1H), 6.42(s, 1H), 3.74 (s, 3H); ¹⁹F-NMR: (376 MHz, DMSO-d₆) δ ppm −84.72 (s, 2F)

Example 403

According to the procedure for the preparation of Example 400, couplingof Intermediate 12 (30 mg, 0.064 mmol) and Example 403B (24.8 mg, 0.129mmol) afforded Example 403 (14.7 mg, 55% yield). MS(ESI) m/z: 412.2(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ ¹H-NMR: (500 MHz, DMSO-d₆) δ ppm12.83 (s, 1H), 10.37 (s, 1H), 8.34 (d, J=7.1 Hz, 1H), 7.98 (d, J=8.4 Hz,2H), 7.93-7.84 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.56 (d, J=8.4 Hz, 2H),7.52-7.14 (m, 1H), 6.58 (s, 1H), 3.81 (s, 3H); HPLC RT=1.45 min (MethodE), 1.45 min (Method F).

Example 404:1-(3-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

Example 404A: Ethyl 1-(3-methoxyphenyl)-1H-1,2,3-triazole-4-carboxylate

To the solution of 3-methoxyaniline (0.3 g, 2.44 mmol) in acetonitrile(6 mL) at 0° C. was added isoamyl nitrite (0.327 mL, 2.44 mmol),followed by azidotrimethylsilane (0.320 mL, 2.44 mmol) dropwise. After 5min, the ice bath removed, and the reaction mixture was stirred at rtfor 10 min, then ethyl propiolate (0.494 mL, 4.87 mmol) added. Thereaction mixture stirred in a sealed tube at 80° C. for 20 h, then wascooled to rt. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-40% EtOAc/Hexanes) to afford Example404A. MS(ESI) m/z: 248.0 (M+H)⁺; ¹H NMR (400 MHz, chloroform-d) δ 8.48(s, 1H), 7.42-7.32 (m, 1H), 7.28 (t, J=2.2 Hz, 1H), 7.26-7.19 (m, 1H),6.99-6.88 (m, 1H), 4.38 (q, J=7.0 Hz, 2H), 3.81 (s, 3H), 1.36 (t, J=7.2Hz, 3H).

Example 404B: 1-(3-Methoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid

Example 404A (120 mg, 0.485 mmol) mixed with 1M lithium hydroxide (1.2mL, 1.2 mmol) in THF (2 mL) and THF (2 mL). The reaction mixture wasstirred at rt for 2 h, then was concentrated. The residue was purifiedby flash chromatography (0-20% MeOH/DCM) to afford Example 404B (100 mg,94% yield) as a yellow solid. MS(ESI) m/z: 220.0 (M+H)⁺; ¹H NMR (400MHz, DMSO-d₆) δ 9.03 (s, 1H), 7.59-7.43 (m, 3H), 7.08-7.00 (m, 1H), 3.86(s, 3H).

Example 404

According to the procedure for the preparation of Example 400, couplingof Intermediate 12 (10 mg, 0.028 mmol) and Example 404B (6.9 mg, 0.031mmol) afforded Example 404 (1.9 mg, 15% yield). MS(ESI) m/z: 439.15(M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.90 (s, 1H), 10.88 (s, 1H), 9.59(s, 1H), 8.42 (d, J=7.6 Hz, 1H), 8.13 (d, J=7.9 Hz, 2H), 7.98 (t, J=7.6Hz, 2H), 7.83 (d, J=7.3 Hz, 1H), 7.73-7.64 (m, 4H), 7.61 (d, J=7.0 Hz,1H), 7.19 (d, J=8.2 Hz, 1H), 3.95 (s, 3H); HPLC RT=1.66 min (Method E),1.66 min (Method F).

Example 405:1-(2-Methoxyphenyl)-5-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

Example 405A: Ethyl1-(2-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylate

To the solution of 2-methoxyaniline (0.30 g, 2.44 mmol) in acetonitrile(3 mL) at 0° C. was added isoamyl nitrite (0.360 mL, 2.68 mmol),followed by azidotrimethylsilane (0.352 mL, 2.68 mmol) dropwise. After 5min, the cold bath removed, and the reaction mixture was stirred at rtfor 10 min, then ethyl but-2-ynoate (0.546 g, 4.87 mmol) added, and thereaction mixture was stirred in a sealed tube at 80° C. for 20 h, thencooled to rt. The reaction mixture was concentrated and the residue waspurified by flash chromatography (0-40% EtOAc/Hexanes) to afford 1stpeak at 30% EtOAc and 2nd peak at 35% EtOAc.

1st Peak:

Ethyl 1-(2-methoxyphenyl)-4-methyl-1H-1,2,3-triazole-5-carboxylate (55mg, 8.6% yield) yellow solid. MS(ESI) m/z: 262.2 (M+H)⁺; ¹H NMR (400MHz, chloroform-d) δ 7.47 (ddd, J=8.3, 7.6, 1.8 Hz, 1H), 7.40 (dd,J=7.7, 1.8 Hz, 1H), 7.08 (td, J=7.6, 1.2 Hz, 1H), 7.01 (dd, J=8.4, 1.1Hz, 1H), 4.21 (q, J=7.3 Hz, 2H), 3.74 (s, 3H), 2.62 (s, 3H), 1.16 (t,J=7.2 Hz, 3H).

2nd Peak:

Example 405A (0.177 g, 28% yield) yellow solid. MS(ESI) m/z: 262.2(M+H)⁺; ¹H NMR δ 7.57-7.50 (m, 1H), 7.36 (dd, J=7.8, 1.7 Hz, 1H),7.16-7.07 (m, 2H), 4.46 (q, J=7.0 Hz, 2H), 3.80 (s, 3H), 2.42 (s, 3H),1.45 (t, J=7.2 Hz, 3H).

Example 405B:1-(2-Methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid

Example 405A (177 mg, 0.677 mmol) stirred with 1M LiOH in THF (2 mL) atrt for 3 h. The reaction mixture was acidified with TFA, then wasconcentrated. The residue was purified via preparative HPLC to affordExample 405B. MS(ESI) m/z: 234.1 (M+H)⁺; ¹H NMR (400 MHz, methanol-d₄) δ7.64-7.57 (m, 1H), 7.40 (dd, J=7.7, 1.5 Hz, 1H), 7.31-7.25 (m, 1H), 7.16(td, J=7.6, 1.1 Hz, 1H), 3.83 (s, 3H), 2.38 (s, 3H).

Example 405

Intermediate 12 (12 mg, 0.051 mmol), Example 405B (13 mg, 0.056 mmol),HATU (21 mg, 0.056 mmol) were mixed in DMF (1.5 mL), add DIEA (0.044 mL,0.253 mmol), stirred 45° C. for 4 h. The reaction mixture was purifiedby preparative HPLC to afford Example 405 (7.1 mg, 31% yield). MS(ESI)m/z: 453.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.35 (d,J=7.4 Hz, 1H), 8.03 (d, J=8.4 Hz, 2H), 7.95-7.91 (m, 2H), 7.77 (d, J=8.1Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.50 (d, J=7.4Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.21 (t, J=7.6 Hz, 1H), 3.82 (s, 3H),2.39 (s, 3H); HPLC RT=1.67 min (Method E), 1.58 min (Method F).

Example 406:1-(2-Methoxyphenyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-1,2,3-triazole-4-carboxamide

According to the procedure for the preparation of Example 404,substituting 2-methoxyaniline for 3-methoxyaniline afforded Example 406.MS(ESI) m/z: 439.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.87 (s, 1H),10.77 (s, 1H), 9.04 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.02 (d, J=8.4 Hz,2H), 7.95-7.90 (m, 2H), 7.76 (d, J=7.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H),7.64-7.56 (m, 3H), 7.36 (d, J=8.4 Hz, 1H), 7.19 (t, J=7.7 Hz, 1H), 3.88(s, 3H); HPLC RT=1.51 min (Method E), 1.51 min (Method F).

Example 407:3-Cyclopropyl-1-methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-5-carboxamide

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then 3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylic acid (21.4 mg,0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirringfor 5 min at rt, HATU (37 mg, 0.097 mmol) was added, and the reactionmixture was stirred at 60° C. for 3 h. The reaction mixture was quenchedwith MeOH (0.1 mL), diluted with DMF, filtered and purified bypreparative HPLC to afford Example 407 (21.7 mg, 87% yield). MS(ESI)m/z: 386.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.85 (s, 1H), 10.33 (s,1H), 8.34 (d, J=7.1 Hz, 1H), 7.97-7.83 (m, 4H), 7.73 (d, J=7.7 Hz, 1H),7.58 (d, J=8.4 Hz, 2H), 6.78 (s, 1H), 3.99 (s, 3H), 1.97-1.83 (m, 1H),0.96-0.82 (m, 2H), 0.67 (d, J=3.7 Hz, 2H); HPLC RT=1.47 min (Method E),1.48 min (Method F).

Example 408:1-Methyl-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid(25.0 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. Afterstirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and thereaction mixture was stirred at 60° C. for 3 h. The reaction mixture wasquenched with MeOH (0.1 mL), diluted with DMF, filtered and purified bypreparative HPLC to afford Example 408 (19.6 mg, 73% yield). MS(ESI)m/z: 414.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.86 (s, 1H), 10.64 (s,1H), 8.34 (d, J=7.1 Hz, 1H), 7.98-7.84 (m, 4H), 7.73 (d, J=7.7 Hz, 1H),7.61 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 4.18 (s, 3H); HPLC RT=1.68 min(Method E), 1.68 min (Method F).

Example 409:N-(4-(4-Oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxylic acid (25.0mg, 0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. Afterstirring for 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and thereaction mixture was stirred at 60° C. for 3 h. The reaction mixture wasquenched with MeOH (0.1 mL), diluted with DMF, filtered and purified bypreparative HPLC to afford Example 409 (21.2 mg, 79% yield). MS(ESI)m/z: 414.1 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.82 (s, 1H), 10.32 (s,1H), 8.34 (d, J=7.3 Hz, 1H), 8.03 (br. s., 1H), 7.98 (d, J=7.6 Hz, 2H),7.90 (t, J=7.6 Hz, 2H), 7.75 (d, J=7.3 Hz, 1H), 7.57 (d, J=7.9 Hz, 2H),6.95 (br. s., 1H), 5.28 (q, J=8.5 Hz, 2H); HPLC RT=1.46 min (Method E),1.47 min (Method F).

Example 410:1-(Difluoromethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (20.9 mg,0.129 mmol) and DIEA (0.068 mL, 0.387 mmol) were added. After stirringfor 5 min at rt, HATU (36.8 mg, 0.097 mmol) was added, and the reactionmixture was stirred at 60° C. for 3 h. The reaction mixture was quenchedwith MeOH (0.1 mL), diluted with DMF, filtered and purified bypreparative HPLC to afford Example 410 (16.6 mg, 67% yield). MS(ESI)m/z: 382.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 12.84 (s, 1H), 10.58 (s,1H), 8.44 (d, J=2.4 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.09-7.80 (m, 5H),7.75 (d, J=7.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.06 (d, J=2.0 Hz, 1H);HPLC RT=1.34 min (Method E), 1.25 min (Method F).

Example 411:1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-5-carboxamide

Example 411A: Methyl 1-(2,2-difluoroethyl)-1H-pyrazole-3-carboxylateExample 411B: Methyl 1-(2,2-difluoroethyl)-1H-pyrazole-5-carboxylate

Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved indry MeCN (30 mL), then 2,2-difluoroethyl trifluoromethanesulfonate(0.633 mL, 4.76 mmol) was added, followed by cesium carbonate (1.94 g,5.95 mmol) and the reaction mixture was stirred at 60° C. for 2 h. Thereaction mixture was cooled to rt, diluted with EtOAc. Then CELITE® wasadded, and solvent was removed under reduced pressure. The residue waspurified by flash chromatography (solid loading on CELITE®): 0-60%EtOAc/Hex affording two products.

Example 411A

(0.271 g, 1.425 mmol, 35.9% yield) as a colorless syrup: peak 1 elutedat ˜25% EtOAc. MS(ESI) m/z: 190.9 (M+H)⁺; ¹H-NMR: (400 MHz, CDCl₃) δ ppm7.57 (d, J=2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.31-5.95 (m, 1H), 4.98(td, J=13.1, 4.4 Hz, 2H), 3.91 (s, 3H); ¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm−122.87 (s, 2F).

Example 411B

(0.398 g, 2.093 mmol, 52.8% yield) as a colorless syrup: peak 2 elutedat ˜45% EtOAc. MS(ESI) m/z: 190.9 (M+H)⁺; ¹H-NMR: (400 MHz, CDCl₃) δ ppm7.51 (d, J=2.4 Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.29-5.94 (m, 1H), 4.55(td, J=13.4, 4.3 Hz, 2H), 3.94 (s, 3H); ¹⁹F-NMR: (376 MHz, CDCl₃) δ ppm−122.42 (s, 2F).

Example 411C: 1-(2,2-Difluoroethyl)-1H-pyrazole-5-carboxylic acid

Example 411A (0.398 g, 2.093 mmol) was dissolved in THF (8.7 ml) andMeOH (1.7 ml), then LiOH (1 M in water) (6.28 ml, 6.28 mmol) was added.The reaction was heated to 50° C. for 2 h. The reaction mixture wasquenched with TFA (0.484 ml, 6.28 mmol), and concentrated under reducedpressure. The residue was diluted with DMSO/MeOH/water, and was purifiedby preparative to afford Example 411C (0.173 g, 46.9% yield) as a whitesolid. MS(ESI) m/z: 176.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.59 (br.s., 1H), 7.64 (d, J=2.0 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.60-6.12 (m,1H), 4.98 (td, J=14.5, 4.0 Hz, 2H).

Example 411

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then Example 411C (22.7 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097mmol) was added, and the reaction mixture was stirred at 60° C. for 3 h.The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,filtered and purified by preparative HPLC to afford Example 411 (16.6mg, 67% yield). MS(ESI) m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.85 (s, 1H), 10.56 (s, 1H), 8.35 (d, J=7.1 Hz, 1H), 7.98-7.85 (m, 4H),7.74 (d, J=8.1 Hz, 1H), 7.71 (d, J=1.7 Hz, 1H), 7.61 (d, J=8.4 Hz, 2H),7.20 (d, J=1.7 Hz, 1H), 6.56-6.25 (m, 1H), 5.03 (td, J=14.6, 3.5 Hz,2H); HPLC RT=1.38 min (Method E), 1.28 min (Method F).

Example 412:1-(2,2-Difluoroethyl)-N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)-1H-pyrazole-3-carboxamide

Example 412A: 1-(2,2-Difluoroethyl)-1H-pyrazole-3-carboxylic acid

Example 411B (0.271 g, 1.43 mmol) was dissolved in THF (5.9 ml) and MeOH(1.2 ml), then LiOH (1 M in water) (4.28 ml, 4.28 mmol) was added. Thereaction was heated to 50° C. for 2 h. The reaction mixture was quenchedwith TFA (0.329 ml, 4.28 mmol), and concentrated under reduced pressure.The residue was diluted with DMSO/MeOH/water, and was purified bypreparative HPLC to afford Example 412A (0.177 g, 71% yield) as a whitesolid. MS(ESI) m/z: 176.9 (M+H)⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.76 (s,1H), 7.88 (d, J=2.4 Hz, 1H), 6.75 (d, J=2.4 Hz, 1H), 6.59-6.19 (m, 1H),4.72 (td, J=15.2, 3.7 Hz, 2H).

Example 412

Intermediate 12, 2 TFA (30 mg, 0.064 mmol) was dissolved in dry DMF (1mL), then Example 412A (22.7 mg, 0.129 mmol) and DIEA (0.068 mL, 0.387mmol) were added. After stirring for 5 min at rt, HATU (36.8 mg, 0.097mmol) was added, and the reaction mixture was stirred at 60° C. for 3 h.The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF,filtered and purified by preparative HPLC to afford Example 412 (23.3mg, 91% yield). MS(ESI) m/z: 396.2 (M+H)⁺; ¹H NMR (500 MHz, DMSO-d₆) δ12.79 (s, 1H), 10.26 (s, 1H), 8.30 (d, J=7.1 Hz, 1H), 7.99-7.81 (m, 5H),7.71 (d, J=7.7 Hz, 1H), 7.53 (d, J=8.4 Hz, 2H), 6.86 (d, J=2.0 Hz, 1H),6.58-6.30 (m, 1H), 4.74 (td, J=15.1, 3.2 Hz, 2H); HPLC RT=1.31 min(Method E), 1.31 min (Method F).

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: M is N; L is selected from —CR⁴R⁴C(O)—, —OC(O)—,—NR⁶C(O)—, and —NR⁶—; R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle and 4-to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p); wherein said carbocycle andheterocycle are substituted with 1-4 R⁷; R², at each occurrence, isindependently selected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, C₁₋₄ haloalkyl, —OH, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂,—NH(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl),—CO(C₁₋₄ alkyl), —CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂,—OCH₂CO₂H, —NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl),—SO₂NH₂, —C(═NH)NH₂, carbocycle, and heterocycle, wherein said alkyl,alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R³, at each occurrence, is independentlyselected from halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄haloalkyl, —CH₂OH, —OCH₂F, —OCHF₂, —OCF₃, CN, —NH₂, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, —CO₂H, —CH₂CO₂H, —CO₂(C₁₋₄ alkyl), —CO(C₁₋₄ alkyl),—CH₂NH₂, —CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —OCH₂CO₂H,—NHCO(C₁₋₄ alkyl), —NHCO₂(C₁₋₄ alkyl), —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂,—C(═NH)NH₂, carbocycle, and heterocycle, wherein said alkyl, alkoxy,alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁴, at each occurrence, is independently selected from H, OH,NH₂, CH₂NH₂, C₁₋₄ haloalkyl, OCH₂F, OCHF₂, OCF₃, —NH(C₁₋₄ alkyl),—N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, CH₂OH, CH₂O(C₁₋₄ alkyl), CH₂CO₂H,CH₂CO₂(C₁₋₄ alkyl), C₁₋₄ alkyl, carbocycle, and heterocycle, whereinsaid alkyl, alkoxy, haloalkyl, carbocycle, and heterocycle aresubstituted with 0-4 R⁹; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 15-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, —(CH₂)_(n)—C(O)C₁₋₄alkyl,—(CH₂)_(n)—C(O)carbocycle, —(CH₂)_(n)—C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), —(CH₂)_(n)—C(O)O-alkyl,—(CH₂)_(n)—C(O)O-carbocycle, —(CH₂)_(n)—C(O)O-heterocycle,—(CH₂)_(n)—SO₂alkyl, —(CH₂)_(n) SO₂carbocycle,—(CH₂)_(n)—SO₂heterocycle, —(CH₂)_(n)—SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,alkenyl, alkynyl, carbocycle, and heterocycle are substituted with 0-4R⁹; alternatively, R⁸ and R⁸ are taken together with the nitrogen atomto which they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)carbocycle, —O(CH₂)_(n)heterocycle,—O(CH₂)_(n)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl; R^(a), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH,CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b); R^(b), at each occurrence, isindependently selected from ═O, OH, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl),CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c); R^(c), at eachoccurrence, is independently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halogen, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), andheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; p, ateach occurrence, is independently selected from 0, 1, and 2; providedwhen L is NHC(O), R¹ is other than

wherein X is N or a substituted or unsubstituted carbon atom; when L isNR⁶, R¹ is heterocycle substituted with 1-4 R⁷;
 2. The compound of claim1, having Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein: M is N; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle,SO₂alkyl, SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a),—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; R⁹, at eachoccurrence, is independently selected from halogen, OH, NO₂, CHF₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R¹⁰ is selected from H and C₁₋₄ alkyl; R^(a), at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, —(CH₂)_(n)OH,CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄ alkyl), —CONH₂, —CONH—C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), R^(c),CO₂R^(c), and CONHR^(c); alternatively, R^(a) and R^(a) are takentogether with the nitrogen atom to which they are attached to form 4- to10-membered heterocycle, wherein said alkyl, alkylene, and heterocycleare substituted with 0-4 R^(b); R^(b), at each occurrence, isindependently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, OCF₃,NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄ haloalkyl), CO₂(C₁₋₄alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄ alkyl)₂, —CONH—C₁₋₄alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄ alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄alkyl), —R^(c), COR^(c), CO₂R^(c), and CONHR^(c); R^(c), at eachoccurrence, is independently selected from —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to 6-membered heterocyclecontaining carbon atoms and 1-4 heteroatoms selected from the groupconsisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); wherein each ringmoiety is substituted with 0-2 R^(d); R^(d), at each occurrence, isindependently selected from ═O, halogen, —OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and —NHCO(C₁₋₄ alkyl), andheterocycle containing carbon atoms and 1-4 heteroatoms selected fromthe group consisting of: N, NH, N(C₁₋₄ alkyl), O, and S(O)_(p); n, ateach occurrence, is independently selected from 0, 1, 2, 3, and 4; p, ateach occurrence, is independently selected from 0, 1, and
 2. 3. Thecompound of claim 2, wherein: R⁵ is selected from H, C₁₋₄ alkyl,—(CH₂)_(n)—C₃₋₁₀ cycloalkyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-4-10 memberedheterocycle selected from

wherein said alkyl, cycloalkyl, aryl are substituted with 1-4 R⁷.
 4. Thecompound of claim 2, wherein: R⁵ and R⁵ are taken together with thenitrogen atom to which they are attached to form a heterocycle selectedfrom

R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —CH₂NH₂, —NHCO(C₁₋₄alkyl), —NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl),—(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle,—NHCO-carbocycle, —NHCO-heterocycle, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; R⁸, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)—C(O)NR^(a)R^(a),C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl,SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle,and —(CH₂)_(n)-heterocycle, wherein said alkyl, carbocycle, andheterocycle are substituted with 0-4 R⁹; alternatively, R⁸ and R⁸ aretaken together with the nitrogen atom to which they are attached to form4- to 10-membered heterocycle substituted with 0-4 R⁹; and R⁹, at eachoccurrence, is independently selected from halogen, OH, NO₂, CHF₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R^(a), at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, —(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄alkyl), —CONH₂, —CONH—C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R^(c), and CONHR^(c); alternatively,R^(a) and R^(a) are taken together with the nitrogen atom to which theyare attached to form 4- to 10-membered heterocycle, wherein said alkyl,alkylene, and heterocycle are substituted with 0-4 R^(b); R^(b), at eachoccurrence, is independently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c); R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); andR^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p).
 5. The compound of claim 1, having Formula (III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: M is N; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹; R⁹, at each occurrence, is independently selected from halogen, OH,NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl),CONH₂, —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—O(CH₂)_(n)heterocycle, —O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b); n, at each occurrence, isindependently selected from 0, 1, 2, 3, and 4; and p, at eachoccurrence, is independently selected from 0, 1, and
 2. 6. The compoundof claim 1, wherein: L is —NR⁶—; R¹ is heteroaryl substituted with 1-4R⁷; R⁷, at each occurrence, is independently selected from H, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, —(CH₂)_(n)-carbocycle, and—(CH₂)_(n)-heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R⁹.
 7. The compound of claim 6,wherein: L is —NR⁶—; and R¹ is selected from


8. The compound of claim 1, having Formula (IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: R¹ is selected from NR⁵R⁵, C₃₋₁₀ carbocycle, and 5- to10-membered heterocycle, wherein said carbocycle and heterocycle aresubstituted with 1-4 R⁷; R⁵, at each occurrence, is independentlyselected from H, C₁₋₄ alkyl, —(CR⁶R⁶)_(n)—C₃₋₁₀ carbocycle, and—(CR⁶R⁶)_(n)-4-10 membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, NR⁸, O, and S(O)_(p), wherein said alkyl,carbocycle, and heterocycle are substituted with 1-4 R⁷; alternatively,R⁵ and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁶, at each occurrence, is independently selected from H and C₁₋₄ alkyl;R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C₂₋₄ alkenyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, alkenyl, carbocycle, and heterocycle are substitutedwith 0-4 R⁹; R⁹, at each occurrence, is independently selected fromhalogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H,CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a),—O(CH₂)_(n)heterocycle, —O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10membered heterocycle, wherein said alkyl, alkoxyl, carbocycle, andheterocycle are substituted with 0-4 R^(b); n, at each occurrence, isindependently selected from 0, 1, 2, 3, and 4; p, at each occurrence, isindependently selected from 0, 1, and
 2. 9. The compound of claim 8,wherein: R¹ is selected from

R⁷, at each occurrence, is independently selected from H, ═O, NO₂,halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHCO₂(CH₂)₂O (C₁₋₄ alkyl), —NHCO₂(CH₂)₃O(C₁₋₄ alkyl), —NHCO₂(CH₂)₂OH, —NHCO₂(CH₂)₂NH₂, —NHCO₂(CH₂)₂N(C₁₋₄alkyl)₂, —NHCO₂CH₂CO₂H, —CH₂NHCO₂(C₁₋₄ alkyl), —NHC(O)NR⁸R⁸, —NHSO₂(C₁₋₄alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl), —SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH,—SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —(CH₂)_(n)—CONR⁸R⁸, —O(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle,—(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, NR⁸, O, and S(O)_(p), whereinsaid alkyl, alkoxyl, carbocycle, and heterocycle are substituted with0-4 R⁹; R⁸, at each occurrence, is independently selected from H, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)carbocycle, C(O)heterocycle,—(CH₂)_(n)—C(O)NR^(a)R^(a), C(O)O-alkyl, C(O)O-carbocycle,C(O)O-heterocycle, SO₂alkyl, SO₂carbocycle, SO₂heterocycle,SO₂NR^(a)R^(a), —(CH₂)_(n)-carbocycle, and —(CH₂)_(n)-heterocycle,wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4R⁹; alternatively, R⁸ and R⁸ are taken together with the nitrogen atomto which they are attached to form 4- to 10-membered heterocyclesubstituted with 0-4 R⁹; and R⁹, at each occurrence, is independentlyselected from halogen, OH, NO₂, CHF₂, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy,CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂, —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b); R^(a), at each occurrence, is independently selectedfrom H, C₁₋₄ alkyl, —(CH₂)_(n)OH, CO(C₁₋₄ alkyl), COCF₃, CO₂(C₁₋₄alkyl), —CONH₂, —CONH—C₁₋₄ alkylene-CO₂(C₁₋₄ alkyl), C₁₋₄alkylene-CO₂(C₁₋₄ alkyl), R^(c), CO₂R^(c), and CONHR^(c); alternatively,R^(a) and R^(a) are taken together with the nitrogen atom to which theyare attached to form 4- to 10-membered heterocycle, wherein said alkyl,alkylene, and heterocycle are substituted with 0-4 R^(b); R^(b), at eachoccurrence, is independently selected from ═O, halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, OCF₃, NH₂, NO₂, N(C₁₋₄ alkyl)₂, CO(C₁₋₄ alkyl), CO(C₁₋₄haloalkyl), CO₂(C₁₋₄ alkyl), CONH₂, —CONH(C₁₋₄ alkyl), —CON(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-O(C₁₋₄ alkyl), —CONH—C₁₋₄ alkylene-N(C₁₋₄alkyl)₂, —CONH—C₁₋₄ alkylene-N (C₁₋₄ alkyl)₂, —C₁₋₄alkylene-O—P(O)(OH)₂, —NHCO₂(C₁₋₄ alkyl), —R^(c), COR^(c), CO₂R^(c), andCONHR^(c); R^(c), at each occurrence, is independently selected from—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)-phenyl, and —(CH₂)_(n)-5- to6-membered heterocycle containing carbon atoms and 1-4 heteroatomsselected from the group consisting of: N, NH, N(C₁₋₄ alkyl), O, andS(O)_(p); wherein each ring moiety is substituted with 0-2 R^(d); andR^(d), at each occurrence, is independently selected from ═O, halogen,—OH, C₁₋₄ alkyl, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ alkoxy, and—NHCO(C₁₋₄ alkyl), and heterocycle containing carbon atoms and 1-4heteroatoms selected from the group consisting of: N, NH, N(C₁₋₄ alkyl),O, and S(O)_(p).
 10. The compound of claim 8, wherein: R¹ is NR⁵R⁵; R⁵and R⁵ are taken together with the nitrogen atom to which they areattached to form 4- to 10-membered heterocycle substituted with 1-4 R⁷;R⁷, at each occurrence, is independently selected from H, ═O, halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, CN, OH, CF₃, —(CH₂)_(n)—CO₂H,—(CH₂)_(n)—CO₂(C₁₋₄ alkyl), —(CH₂)_(n)—NR⁸R⁸, —NHCO(C₁₋₄ alkyl),—NHCOCF₃, —NHCO₂(C₁₋₄ alkyl), —NHC(O)NH₂, —NHC(O)NH(C₁₋₄ alkyl),—NHC(O)N(C₁₋₄ alkyl)₂, —NHSO₂(C₁₋₄ alkyl), —SO₂NH₂, —SO₂NH(C₁₋₄ alkyl),—SO₂N(C₁₋₄ alkyl)₂, —SO₂NH(CH₂)₂OH, —SO₂NH(CH₂)₂O (C₁₋₄ alkyl), —CONH₂,—CONH(C₁₋₄ alkyl), —CON(C₁₋₄ alkyl)₂, —CH₂CONH₂, —(CH₂)_(n)-carbocycle,—O(CH₂)_(n)-carbocycle, —O(CH₂)_(n)-heterocycle, and—(CH₂)_(n)-heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, NR⁸, O, and S(O)_(p), wherein said alkyl, alkoxyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; R⁸, at eachoccurrence, is independently selected from H, C₁₋₄ alkyl, C(O)C₁₋₄alkyl,C(O)carbocycle, C(O)heterocycle, —(CH₂)_(n)—C(O)NR^(a)R^(a),C(O)O-alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO₂alkyl,SO₂carbocycle, SO₂heterocycle, SO₂NR^(a)R^(a), —(CH₂)_(n)-cycloalkyl,—(CH₂)_(n)-phenyl, and —(CH₂)_(n)-heterocycle, wherein said alkyl,carbocycle, and heterocycle are substituted with 0-4 R⁹; and R⁹, at eachoccurrence, is independently selected from halogen, OH, NO₂, CHF₂, CF₃,C₁₋₄ alkyl, C₁₋₄ alkoxy, CH₂OH, CO₂H, CO₂(C₁₋₄ alkyl), CONH₂,—(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CONR^(a)R^(a), —O(CH₂)_(n)heterocycle,—O(CH₂)(2-4)NR^(a)R^(a), —(CR¹⁰R¹⁰)_(n)-4-10 membered heterocycle,wherein said alkyl, alkoxyl, carbocycle, and heterocycle are substitutedwith 0-4 R^(b).
 11. A pharmaceutical composition comprising one or morecompounds according to claim 1 and a pharmaceutically acceptable carrieror diluent.
 12. A method for the_prophylaxis and/or treatment ofdisorders associated with aberrant Rho kinase activity, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of claim 1 or a stereoisomer, a tautomer, or apharmaceutically acceptable salt thereof.
 13. The method of claim 12,wherein said disorder is selected from the group consisting of acardiovascular disorder, a smooth muscle related disorder, a fibroticdisease, an inflammatory disease, neuropathic disorders, oncologicdisorders, and an autoimmune disorder.
 14. A method for inhibiting Rhokinase activity, comprising (a) providing target cells and a compositioncomprising a compound described in claim 1; and (b) exposing said targetcells to said composition under conditions such that said compositionbinds to said target cells so as to inhibit Rho kinase activity withinsaid target cells.